Pyrazole derivatives as h4 antagonist compounds

ABSTRACT

The disclosures herein relate to novel compounds of formula (1): and salts thereof, wherein A; X; n; R 1  and R 2  are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with H4 receptors.

This application relates to novel compounds and their use as HistamineH4 receptor antagonists. Compounds described herein may be useful in thetreatment or prevention of diseases in which H4 receptors are involved.The application is also directed to pharmaceutical compositionscomprising these compounds and the manufacture and use of thesecompounds and compositions in the prevention or treatment of suchdiseases in which H4 receptors are involved.

BACKGROUND OF THE INVENTION

Histamine is a short-acting biogenic amine generated in mast cells whereit is stored in cytosolic granules and released in response to variousimmunological and non-immunological stimuli. Histamine release from mastcells has been traditionally associated with mild to severe signs andsymptoms that characterize hypersensitivity reactions, includingerythema, urticaria, itching, tachycardia, hypotension, ventricularfibrillations, bronchospasm, and cardiac and respiratory arrest. Todate, numerous additional sources have been identified, includingbasophils, neurons and cancer cells. In addition to modulating a widerange of physiological processes, histamine is implicated inpathological conditions including allergies and anaphylaxis, asthma andchronic inflammation, autoimmune, cardiovascular, neuropsychiatric andendocrine disorders as well as cancer.

Histamine exerts its pleiotropic actions mainly through binding to fourtypes of G-protein-coupled receptors (GPCRs), designated as H1-H4 thatare differentially expressed in various cell types and exhibitconsiderable variations among species. The H2 receptor is responsiblefor gastric acid secretion; the H3 receptor controls the release ofhistamine and other neuromodulators in the CNS and the H1 receptor isassociated with wakefulness and inflammatory response.

Identified in 2000, the high affinity H4 receptor displays constitutiveactivity and is expressed mostly, but not exclusively on cells of theimmune system including mast cells, monocytes, dendritic cells,eosinophils, basophils, neutrophils, and T cells. This discovery led tothe attractive prospect of a new drug target with therapeutic potentialin acute and chronic inflammation, autoimmune disease, host defense andneuropathic pain.

The H4R shares only 40% homology with its nearest neighbour the H3R andneither H2 nor H1 antagonists were shown to inhibit histamine inducedeosinophil chemotaxis. Histamine has been shown to inhibitforskolin-induced cAMP responses in a pertussis toxin (PTx)-sensitivemanner, suggesting that H4R signals via heterotrimeric Gαi/o proteins.Transient expression of the H4R in heterologous cell systems (e.g.HEK293 cells) is a widely used method to measure H4 ligand signaling andbinding to generate estimates of functional potency and receptoraffinity respectively.

The discovery of H4R antagonists using these techniques and their studyin various animal disease models including asthma, chronic pruritus,dermatitis, rheumatoid arthritis, gastric ulcerogenesis and colitis hasconfirmed H4R antagonism leads to a profound anti-inflammatory effectand has validated the therapeutic benefit for targeting this receptor.The first H4R antagonist phase 2a clinical trial in patients sufferingfrom moderate-to-severe atopic dermatitis has already been conducted,further confirming H4 as a druggable target in patients

Notwithstanding a number of published H4R ligands, there remains a needto develop new H4R antagonists with good drug candidate quality. Theseantagonists should display excellent low nM potency and affinity withfull selectivity against H1-H3 receptors. They should display no agonistactivity due to risks associated with the induction of pro-inflammatoryresponses, and ideally display a similar pharmacological profile acrossspecies to support PK/PD in various animal models of disease. Theyshould be metabolically stable, with excellent PK, non-toxic and showexcellent H4 specificity in broad safety panel profiling.

The human ether-a-go-go-related gene (hERG) encodes the pore-formingsubunit of the rapidly activating delayed rectifier potassium channel(IKr), which plays an important role in ventricular repolarisation andin determining the QT-interval of the electrocardiogram with QT-intervalbeing the time taken for ventricular depolarisation and repolarisation.It is widely acknowledged that hERG is highly susceptible to inhibitionby a wide range of structurally diverse compounds. When the channelsability to conduct electrical current across the cell membrane isinhibited or compromised by application of drugs, it can result in apotentially fatal disorder called QT syndrome. A number of clinicallysuccessful drugs in the market have had the tendency to inhibit hERG,and create a concomitant risk of sudden death, as a side-effect, whichhas made hERG inhibition an important anti-target that must be avoidedduring drug development.

Compounds of the invention are antagonists of the H4 receptor. Certaincompounds have a low hERG inhibition, making these particularlybeneficial.

THE INVENTION

The present invention provides compounds having activity as H4 receptorantagonists. More particularly, the invention provides compounds thatcombine H4 receptor antagonism with low hERG activity.

Accordingly, in one embodiment the invention provides a compound of theformula (1)

or a salt thereof, wherein;

X is CH or N;

n is 1 or 2;

R¹ is selected from H or C₁₋₃ alkyl, wherein the C₁₋₃ alkyl group may becyclised back onto the ring to which NHR¹ is attached to form a secondring;

R² is H or methyl; and

A represents an optionally substituted pyrazole ring.

Ring A can represent an optionally substituted pyrazole ring which islinked to the ring containing X by a carbon-carbon bond.

Particular compounds include a compound of formula (1a):

or salts thereof, wherein A, X, R¹ and R² are as defined above.

Particular compounds also include compounds of formula (2a), (2b) and(2c):

or a salt thereof, wherein A and X are as defined above.

Particular isomers include compounds of formula (3a), (3b) and (3c):

or a salt thereof, wherein A and X are as defined above.

Particular compounds include a compound of formula (1b):

or a salt thereof, wherein A, X, R¹ and R² are as defined above.

Particular compounds also include compounds of formula (2d) and (2e):

or a salt thereof, wherein A and X are as defined above.

In the compounds herein, R¹ can be H or C₁₋₃ alkyl.

In the compounds herein, R¹ can be methyl, ethyl, propyl, isopropyl orcyclopropyl.

In the compounds herein, R¹ can be C₁₋₃ alkyl, wherein the C₁₋₃ alkylgroup is cyclised back onto the ring to which NHR¹ is attached to form asecond ring.

In the compounds herein, R² can be H or methyl.

Ring A represents an optionally substituted pyrazole ring.

Ring A may represent a ring selected from:

or a tautomer thereof.

Ring A may represent a ring selected from:

wherein R³ is selected from H; a C₁₋₆ non-aromatic hydrocarbon groupoptionally substituted with 1 to 6 fluorine atoms; (CH₂)_(m)R⁶, whereinm is 1 to 3 and R⁶ is selected from CN, OH, C₁-C₃ alkoxy and a group SR⁸or oxidized forms thereof, wherein R⁸ is C₁-C₃ alkyl; an optionallysubstituted 4 to 6 membered saturated heterocyclic ring containing 1heteroatom selected from O and N, wherein the optional substituent isCO₂R⁷, wherein R⁷ is C₁₋₃ alkyl; wherein R⁴ and R⁵ are independentlyselected from: a C₁₋₆ non-aromatic hydrocarbon group optionallysubstituted with 1 to 6 fluorine atoms; (CH₂)_(p)R⁹, wherein p is 0 to 3and R⁹ is selected from CN, halo, OH, C₁-C₃ alkoxy and a group SR⁸ oroxidized forms thereof, wherein R⁸ is C₁-C₃ alkyl; or R⁴ and R⁵ may beoptionally joined to form a fused 5 or 6 membered ring; or R⁴ and R³ maybe optionally joined to form a fused 5 or 6 membered ring.

The compounds may be used as H4 receptor antagonists. The compounds maybe used in the manufacture of medicaments. The compounds or medicamentsmay be for use in treating, preventing, ameliorating, controlling orreducing the risk of inflammatory disorders including asthma, chronicpruritus, dermatitis, rheumatoid arthritis, gastric ulcerogenesis andcolitis.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel compounds. The invention also relates tothe use of novel compounds as antagonists of the H4 receptor. Theinvention further relates to the use of novel compounds in themanufacture of medicaments for use as H4 receptor antagonists or for thetreatment of H4 system dysfunction. The invention further relates tocompounds, compositions and medicaments which are selective H4 receptorantagonists.

The invention further relates to compounds, compositions and medicamentsuseful for the treatment of acute and chronic inflammation, autoimmunedisease, host defense disorders and neuropathic pain.

Compounds of the invention include compounds according to formula (1)

or a salt thereof, wherein;

X is CH or N;

n is 1 or 2;

R¹ is selected from H or C₁₋₃ alkyl, wherein the C₁₋₃ alkyl group may becyclised back onto the ring to which NHR¹ is attached to form a secondring;

R² is H or methyl; and

A represents an optionally substituted pyrazole ring which is linked tothe ring containing X by a carbon-carbon bond.

In the compounds herein X can be CH or N. X can be CH. X can be N.

In the compounds herein n can be 1 or 2. n can be 1. n can be 2.

In the compounds herein R¹ can be H or C₁₋₃ alkyl. The C₁₋₃ alkyl groupmay be cyclised back onto the ring to which NHR¹ is attached to form asecond ring.

In the compounds herein R² can be H or methyl. R² can be H. R² can bemethyl.

Exemplary compounds may include

wherein A represents an optionally substituted pyrazole ring.

In the compounds herein A can be selected from:

or a tautomer thereof.

Ring A may represent a ring selected from:

wherein R³ is selected from H; a C₁₋₆ non-aromatic hydrocarbon groupoptionally substituted with 1 to 6 fluorine atoms; (CH₂)_(m)R⁶, whereinm is 1 to 3 and R⁶ is selected from CN, OH, C₁-C₃ alkoxy and a group SR⁸or oxidized forms thereof, wherein R⁸ is C₁-C₃ alkyl; an optionallysubstituted 4 to 6 membered saturated heterocyclic ring containing 1heteroatom selected from O and N, wherein the optional substituent isCO₂R⁷, wherein R⁷ is C₁₋₃ alkyl; wherein R⁴ and R⁵ are independentlyselected from: a C₁₋₆ non-aromatic hydrocarbon group optionallysubstituted with 1 to 6 fluorine atoms; (CH₂)_(p)R⁹, wherein p is 0 to 3and R⁹ is selected from CN, halo, OH, C₁-C₃ alkoxy and a group SR⁸ oroxidized forms thereof, wherein R⁸ is C₁-C₃ alkyl; or R⁴ and R⁵ may beoptionally joined to form a fused 5 or 6 membered ring; or R⁴ and R³ maybe optionally joined to form a fused 5 or 6 membered ring.

Particular substituents for ring A include one or more of methyl, ethyl,isopropyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl,1-hydroxyethyl, cyclopropyl, cyclobutyl, fluoro, chloro, bromo, cyano,hydroxyl, methoxy, thiomethyl, 1-methyoxyethyl, cyanomethyl,1-cyanoethyl, oxetane, piperidine or a fused ring. The fused ring can bea 6 membered aromatic ring. The fused ring can be a 5 or 6 memberedaliphatic ring. The piperidine substituent may be 3 N-ethyl carboxylate.Where A is substituted with two or three groups, each substituent may bethe same or different.

In the compounds herein R³ can be selected from H, methyl, CF₃, CF₂H,ethyl, cyclopropyl, cyclobutyl, CH₂CF₃, CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CH₂CN,CH₂CN, oxetane, ethyl-piperidine-carboxylate or R⁴ and R³ can be joinedto form a fused 5 membered ring. R⁴ and R³ can be joined to form a fused5 membered aliphatic ring.

In the compounds herein R⁴ or R⁵ can be selected from methyl, ethyl,cyclopropyl, cyclobutyl, propyl, isopropyl, CF₃, CF₂H, fluoro, chloro,bromo, cyano, hydroxy, methoxy, thiomethyl or R⁴ and R⁵ are joined toform a fused 5 or 6 membered ring. R⁴ and R⁵ can be joined to form afused 5 or 6 membered aliphatic or aromatic ring. R⁴ and R⁵ can bejoined to form a fused 5 or 6 membered aliphatic ring. R⁴ and R⁵ can bejoined to form a fused 5 or 6 membered aromatic ring.

In the compounds herein A can be selected from the group consisting of:

Exemplary compounds may include

wherein n is 1 or 2;

R¹ is selected from H or C₁₋₃ alkyl, wherein the C₁₋₃ alkyl group may becyclised back onto the ring to which NHR¹ is attached to form a secondring; and

R² is H or methyl.

The compound can be selected from the group consisting of:

and salts thereof.

Specific examples of compounds include those having low hERG activity.

Particular compounds include:

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of any of the compoundsdescribed herein, including those of the formula (1) or formula (1a), isused to describe any form of intervention where a compound isadministered to a subject suffering from, or at risk of suffering from,or potentially at risk of suffering from the disease or disorder inquestion. Thus, the term “treatment” covers both preventative(prophylactic) treatment and treatment where measurable or detectablesymptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the severityof the pain.

The term “non-aromatic hydrocarbon group” as in “C₁₋₆ non-aromatichydrocarbon group” refers to a group consisting of carbon and hydrogenatoms and which contains no aromatic rings. The hydrocarbon group may befully saturated or may contain one or more carbon-carbon double bonds orcarbon-carbon triple bonds, or mixtures of double and triple bonds. Thehydrocarbon group may be a straight chain or branched chain group or mayconsist of or contain a cyclic group. Thus the term non-aromatichydrocarbon includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl and so on.

The term “saturated” refers to a hydrocarbon group containing nocarbon-carbon double bonds or triple bonds. The saturated hydrocarbongroup can therefore be an alkyl group, a cycloalkyl group, acycloalkylalkyl group, an alkylcycloalkyl group or analkylcycloalkylalkyl group. Examples of saturated hydrocarbon groupsinclude cyclopropyl, cyclobutyl and cyclopropylmethyl.

Examples of 4 to 6 membered saturated heterocyclic rings containing 1heteroatom selected from O and N include oxetane, azetidine,tetrahydrofuran, pyrollidine, tetrahydropyran and piperidine.

To the extent that any of the compounds described have chiral centres,the present invention extends to all optical isomers of such compounds,whether in the form of racemates or resolved enantiomers. The inventiondescribed herein relates to all crystal forms, solvates and hydrates ofany of the disclosed compounds however so prepared. To the extent thatany of the compounds disclosed herein have acid or basic centres such ascarboxylates or amino groups, then all salt forms of said compounds areincluded herein. In the case of pharmaceutical uses, the salt should beseen as being a pharmaceutically acceptable salt.

Salts or pharmaceutically acceptable salts that may be mentioned includeacid addition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound with one or more equivalents of an appropriateacid or base, optionally in a solvent, or in a medium in which the saltis insoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound inthe form of a salt with another counter-ion, for example using asuitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals such as sodium, magnesium, potassium and calcium.

Examples of acid addition salts include acid addition salts formed withacetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g.benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic andp-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic,4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic,(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric,gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g.D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic,hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.(+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.(−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic,4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic,tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valericacids.

Also encompassed are any solvates of the compounds and their salts.Preferred solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent). Examples of suchsolvents include water, alcohols (such as ethanol, isopropanol andbutanol) and dimethylsulfoxide. Solvates can be prepared byrecrystallising the compounds of the invention with a solvent or mixtureof solvents containing the solvating solvent. Whether or not a solvatehas been formed in any given instance can be determined by subjectingcrystals of the compound to analysis using well known and standardtechniques such as thermogravimetric analysis (TGA), differentialscanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates may be hydrates, and examples of hydrates includehemihydrates, monohydrates and dihydrates. For a more detaileddiscussion of solvates and the methods used to make and characterisethem, see Bryn et ai, Solid-State Chemistry of Drugs, Second Edition,published by SSCI, Inc of West Lafayette, Ind., USA, 1999, ISBN0-967-06710-3.

The term “pharmaceutical composition” in the context of this inventionmeans a composition comprising an active agent and comprisingadditionally one or more pharmaceutically acceptable carriers. Thecomposition may further contain ingredients selected from, for example,diluents, adjuvants, excipients, vehicles, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms. The compositions may take the form, for example, oftablets, dragees, powders, elixirs, syrups, liquid preparationsincluding suspensions, sprays, inhalants, tablets, lozenges, emulsions,solutions, cachets, granules, capsules and suppositories, as well asliquid preparations for injections, including liposome preparations.

The compounds of the invention may contain one or more isotopicsubstitutions, and a reference to a particular element includes withinits scope all isotopes of the element. For example, a reference tohydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. In an analogous manner, a reference toa particular functional group also includes within its scope isotopicvariations, unless the context indicates otherwise. For example, areference to an alkyl group such as an ethyl group or an alkoxy groupsuch as a methoxy group also covers variations in which one or more ofthe hydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group) or a methoxygroup in which all three hydrogen atoms are in the deuterium isotopicform (a trideuteromethoxy group). The isotopes may be radioactive ornon-radioactive.

Therapeutic dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with the smaller dosages which are less than the optimum doseof the compound. Thereafter the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The magnitude of an effective dose of a compound will, of course, varywith the nature of the severity of the condition to be treated and withthe particular compound and its route of administration. The selectionof appropriate dosages is within the ability of one of ordinary skill inthis art, without undue burden. In general, the daily dose range may befrom about 10 μg to about 30 mg per kg body weight of a human andnon-human animal, preferably from about 50 μg to about 30 mg per kg ofbody weight of a human and non-human animal, for example from about 50μg to about 10 mg per kg of body weight of a human and non-human animal,for example from about 100 μg to about 30 mg per kg of body weight of ahuman and non-human animal, for example from about 100 μg to about 10 mgper kg of body weight of a human and non-human animal and mostpreferably from about 100 μg to about 1 mg per kg of body weight of ahuman and non-human animal.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment, the invention provides a process forthe preparation of a compound as defined in formula (1) above, whichprocess comprises:

(A) the reaction of a compound of the formula (10):

with a compound of the formula (11):

under SNAr conditions or transition metal catalyzed coupling conditions;wherein A, R¹, R², X, and n are as defined in formula (1) above, and LGrepresents a suitable leaving group; or

(B) the reaction of a compound of the formula (12):

with a compound of the formula (13):

A-M   (13)

under transition metal catalyzed coupling conditions or under SNArconditions; wherein A, R¹, R², X and n are as defined in formula (1)above, LG represents a suitable leaving group and M, which may bepresent or absent, represents a suitably substituted metal or non-metal;or

(C) converting one compound of the formula (1) to another compound ofthe formula (1).

In process variant (A), the compound of formula (10) may be reacted withthe compound of formula (11) under SNAr conditions. The SNAr reaction istypically carried out using either an excess of the compound of formula(11), or a stoichiometric quantity of the compound of formula (11) inthe presence of a base which may be a tertiary amine base such as TEA orDIPEA or an inorganic base such as K₂CO₃, Cs₂CO₃ or NaHCOs, optionallyin a suitable solvent such as H₂O, MeCN, 1,4-dioxane, THF, MeOH, EtOH,IPA, BuOH, DMF, NMP or DMSO, or a combination of suitable solvents, at atemperature between about room temperature to about 200° C., usingconventional heating or optionally by heating with microwaveirradiation, in an open vessel or optionally in a sealed vessel,optionally at a pressure greater than atmospheric pressure, optionallyin the presence of an additive such as KF or a silver salt. Optionally,the compound of formula (11) may be present in the reaction as an acidsalt such as an HCl, HBr or a TFA salt optionally in the presence of atertiary base such as TEA or DIPEA. The leaving group LG in the compoundof formula (10) may be a halogen such as F, Cl or Br; an alkoxy groupsuch as OMe; an aryloxy group such as pentafluorophenoxy; a sulfenylgroup such as SMe, a sulfinyl group such as SOMe, a sulfonyl group suchas SO₂Me, a sulfonyloxy group such as OTs, OMs, ONs or OTf; or a leavinggroup generated by reaction of a hydroxy group with a peptide couplingreagent such as BOP, PyBOP or HATU. Alternatively, in process variant(A), the compound of formula (10) may be reacted with the compound offormula (11) under transition metal catalyzed coupling conditions. Thetransition metal catalyzed coupling reaction is typically carried outusing the compound of formula (11) in the presence of an inorganic basesuch as NaO^(t)Bu, KO^(t)Bu, K₃PO₄, K₂CO₃ or Cs₂CO₃, in a suitablesolvent such as 1,4-dioxane, THF, DME or toluene, or a combination ofsuitable solvents, in the presence of a sub-stoichiometric quantity of atransition metal catalyst such as Pd(OAc)₂, Pd₂(dba)₃, Pd(dppf)Cl₂,Pd(PPh₃)₂Cl₂ or Pd(PPh₃)₄, optionally in the presence of asub-stoichiometric quantity of a phosphine ligand such as PPh₃, PBu₃,P^(t)Bu₃, XPhos, Xantphos or BINAP, at a temperature between about roomtemperature to about 200° C., using conventional heating or optionallyby heating with microwave irradiation, in an open vessel or optionallyin a sealed vessel, optionally at a pressure greater than atmosphericpressure. The leaving group LG in the compound of formula (10) may be ahalogen such as Cl, Br or I, or a sulfonyloxy group such as OTs, OMs,ONs or OTf.

Compounds of formula (10) can be prepared by the reaction shown inScheme 1 below:

Thus, a compound of formula (14), wherein X is as defined in formula (1)above, and LG and LG¹ may be the same or different and representsuitable leaving groups, may be reacted with a compound of formula (13),wherein A is as defined in formula (1) above, and M, which may bepresent or absent, represents a suitably substituted metal or non-metal,under transition metal catalyzed coupling conditions or under SNArconditions to form a compound of formula (10). The transition metalcatalyzed coupling reaction or the SNAr reaction is typically carried asdescribed below in process variant (B), and the compounds of formula(13) and formula (14) may be commercially available or easily preparedby standard methods reported in the published literature from simplestarting materials known to the skilled person. Occasionally, due totheir instability, it may be necessary to generate compounds of formula(13), where M is present, in-situ at low temperatures, e.g. betweenabout −78° C. and room temperature, and react them further in atransition metal catalyzed coupling reaction, without their priorisolation. Details of such methods are known in the publishedliterature, e.g. as reported by Oberli and Buchwald in Org. Lett., 2012,Vol. 14, No. 17, p 4606.

Alternatively, compounds of formula (10), wherein X represents N and LGrepresents Cl, can be typically prepared by the sequence of reactionsshown in Scheme 2 below:

Thus, a carboxylic acid of formula (15) may be homologated to thecorresponding beta-keto ester (16) by first activating it via a numberof standard methods known to the skilled person, e.g. by reaction withCDI in a suitable solvent such as MeCN, and then reacting with a malonicacid derivative such as potassium 3-ethoxy-3-oxopropanoate in thepresence of a Lewis acid such as MgCl₂. Once formed, the beta-keto ester(16) may be cyclised to the amino-hydroxypyrimidine analogue (17) byreaction with guanidine, or an appropriate guanidine salt, in thepresence of a suitable base such as KO^(t)Bu in a suitable solvent suchas MeOH. The amino-hydroxypyrimidine analogue (17) so formed may then bereacted with POCl₃ in the presence or absence of a suitable solvent toform a compound of formula (18). Compounds of formula (15) may becommercially available or easily prepared by standard methods reportedin the published literature from simple starting materials known to theskilled person.

Compounds of formula (11) may be commercially available or easilyprepared by standard methods reported in the published literature fromsimple starting materials known to the skilled person.

In process variant (B), the compound of formula (12) may be reacted withthe compound of formula (13) under transition metal catalyzed couplingconditions. The transition metal catalyzed coupling reaction istypically carried out using the compound of formula (13) wherein M ispresent. For example, when M represents a boronic acid —B(OH)₂, or aboronic ester such as —B(OMe)₂, —B(OiPr)₂ or Bpin, or a lithiumtrialkylborate such as —B(OiPr)₃Li, then the transition metal catalyzedcoupling reaction is typically carried out in the presence of aninorganic base such as NaHCOs, Na₂CO₃, K₂CO₃, Cs₂CO₃ or K₃PO₄, in asuitable solvent such as H₂O, MeCN, 1,4-dioxane, THF, Et₂O, DME, EtOH,IPA, DMF, NMP or toluene, or a combination of suitable solvents, in thepresence of a sub-stoichiometric quantity of a transition metal catalystsuch as Pd(OAc)₂, Pd₂(dba)₃, Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, or atransition metal pre-catalyst such as XPhos Pd G2, optionally in thepresence of a sub-stoichiometric quantity of a phosphine ligand such asPPh₃, P^(t)Bu₃, PCy₃ or XPhos, at a temperature between about roomtemperature to about 200° C., using conventional heating or optionallyby heating with microwave irradiation, in an open vessel or optionallyin a sealed vessel, optionally at a pressure greater than atmosphericpressure. The leaving group LG in the compound of formula (12) may be ahalogen such as Cl, Br or I, or a sulfonyloxy group such as OTs, OMs orOTf.

Alternatively, when M represents a trifluoroborate salt BF₃ ⁻, then thetransition metal catalyzed coupling reaction is typically carried out inthe presence of an inorganic base such as Na₂CO₃, K₂CO₃, Cs₂CO₃ orK₃PO₄, in a suitable solvent such as H₂O, MeCN, 1,4-dioxane, THF, MeOHor EtOH, or a combination of suitable solvents, in the presence of asub-stoichiometric quantity of a transition metal catalyst such asPd(OAc)₂, Pd₂(dba)₃, optionally in the presence of a sub-stoichiometricquantity of a phosphine ligand such as PPh₃, PCy₃ or RuPhos at atemperature between about room temperature to about 200° C., usingconventional heating or optionally by heating with microwaveirradiation, in an open vessel or optionally in a sealed vessel,optionally at a pressure greater than atmospheric pressure. The leavinggroup LG in the compound of formula (12) may be a halogen such as Cl, Bror I.

Alternatively, when M represents a trialkyltin group such as SnMe₃ orSnBu₃, then the transition metal catalyzed coupling reaction istypically carried out in a suitable solvent such 1,4-dioxane, THF, DMF,or toluene, or a combination of suitable solvents, in the presence of asub-stoichiometric quantity of a transition metal catalyst such asPd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃)₂Cl₂ or Pd(PPh₃)₄, optionally in thepresence of an inorganic base such as K₂CO₃ or CsF, optionally in thepresence of an additive such as LiCl, CuI, Bu₄NBr or Et₄NCl, at atemperature between about room temperature to about 200° C., usingconventional heating or optionally by heating with microwaveirradiation, in an open vessel or optionally in a sealed vessel,optionally at a pressure greater than atmospheric pressure. The leavinggroup LG in the compound of formula (12) may be a halogen such as Cl, Bror I.

Alternatively, when M is absent, then the transition metal catalyzedcoupling reaction is typically carried out in the presence of aninorganic base such as NaOtBu, KOtBu, K₃PO₄, K₂CO₃ or Cs₂CO₃, in asuitable solvent such as 1,4-dioxane, THF, DME or toluene, or acombination of suitable solvents, in the presence of asub-stoichiometric quantity of a transition metal catalyst such asPd(OAc)₂, Pd₂(dba)₃, Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂ or Pd(PPh₃)₄, optionallyin the presence of a sub-stoichiometric quantity of a phosphine ligandsuch as PPh₃, PBu₃, PtBu₃, XPhos, Xantphos or BINAP, at a temperaturebetween about room temperature to about 200° C., using conventionalheating or optionally by heating with microwave irradiation, in an openvessel or optionally in a sealed vessel, optionally at a pressuregreater than atmospheric pressure. The leaving group LG in the compoundof formula (12) may be a halogen such as Cl, Br or I, or a sulfonyloxygroup such as OTs, OMs, ONs or OTf.

Alternatively, when M is absent, then the transition metal catalyzedcoupling reaction is typically carried out in the presence of aninorganic base such as K₃PO₄, K₂CO₃ or Cs₂CO₃, in a suitable solventsuch as 1,4-dioxane, DMF, DMSO or toluene, or a combination of suitablesolvents, in the presence of a sub-stoichiometric quantity of atransition metal catalyst such as CuI, optionally in the presence of asub-stoichiometric quantity of an amine such as (S)-proline ortrans-N¹,N²-dimethylcyclohexane-1,2-diamine at a temperature betweenabout room temperature to about 200° C., using conventional heating oroptionally by heating with microwave irradiation, in an open vessel oroptionally in a sealed vessel, optionally at a pressure greater thanatmospheric pressure. The leaving group LG in the compound of formula(12) may be a halogen such as Cl, Br or I.

Alternatively, when M is absent, then the transition metal catalyzedcoupling reaction is typically carried out in the presence of an organicbase such as nBu₄OAc, in a suitable solvent such as 1,4-dioxane, in thepresence of a sub-stoichiometric quantity of a transition metalpre-catalyst such as XPhos Pd G2, optionally in the presence of asub-stoichiometric quantity of a phosphine ligand such as XPhos, at atemperature between about room temperature to about 200° C., usingconventional heating or optionally by heating with microwaveirradiation, in an open vessel or optionally in a sealed vessel,optionally at a pressure greater than atmospheric pressure. The leavinggroup LG in the compound of formula (12) may be a halogen such as Cl.

Alternatively, in process variant (B), the compound of formula (12) maybe reacted with the compound of formula (13) under SNAr conditions. TheSNAr reaction is typically carried out using the compound of formula(13) wherein M is absent, in the presence of a tertiary amine base suchas TEA or DIPEA or an inorganic base such as K₂CO₃, Cs₂CO₃, KOtBu, orNaH in a suitable solvent such as THF, DMF, H2O, DMSO or NMP, or acombination of suitable solvents, at a temperature between about roomtemperature to about 200° C., using conventional heating or optionallyby heating with microwave irradiation, in an open vessel or optionallyin a sealed vessel, optionally at a pressure greater than atmosphericpressure. The leaving group LG in the compound of formula (12) may be ahalogen such as F, Cl or Br; an alkoxy group such as OMe; an aryloxygroup such as pentafluorophenoxy; a sulfenyl group such as SMe, asulfinyl group such as SOMe, a sulfonyl group such as SO₂Me, or asulfonyloxy group such as OTs, OMs, ONs or OTf.

The compound of formula (12) can be prepared by the sequence ofreactions shown in Scheme 3 below:

Thus, a compound of formula (14), wherein X is as defined in formula (1)above, and LG and LG¹ may be the same or different and representsuitable leaving groups, may be reacted with a compound of formula (11),wherein R¹, R² and n are as defined in formula (1) above, under SNArconditions or under transition metal catalyzed coupling conditions toform a compound of formula (12). The SNAr reaction or the transitionmetal catalyzed coupling reaction is typically carried as describedabove in process variant (A).

In process variant (C), one compound of the formula (1) can be convertedinto another compound of the formula (1) by methods well known to theskilled person. Examples of synthetic procedures for converting onefunctional group into another functional group are set out in standardtexts such as March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 7th Edition, Michael B. Smith, John Wiley, 2013, (ISBN:978-0-470-46259-1), Organic Syntheses, Online Edition, www.orgsyn.org,(ISSN 2333-3553) and Fiesers' Reagents for Organic Synthesis, Volumes1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Greene's Protective Groups in Organic Synthesis, Fifth Edition,Editor: Peter G. M. Wuts, John Wiley, 2014, (ISBN: 9781118057483). Inparticular, a useful protecting group for manipulating compounds offormula (10) or formula (12) includes the 2,5-dimethyl-1H-pyrrole group;useful protecting groups for manipulating compounds of formula (11) orformula (12) include BOC and CBZ; and useful protecting groups formanipulating compounds of formula (13) include SEM and THP.

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography),HPLC and SFC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment of the invention, there is provided apharmaceutical composition comprising at least one compound of theformula (1) as defined above together with at least one pharmaceuticallyacceptable excipient.

The composition may be a tablet composition.

The composition may be a capsule composition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragees, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack. The compounds of the formula (1) willgenerally be presented in unit dosage form and, as such, will typicallycontain sufficient compound to provide a desired level of biologicalactivity. For example, a formulation may contain from 1 nanogram to 2grams of active ingredient, e.g. from 1 nanogram to 2 milligrams ofactive ingredient. Within these ranges, particular sub-ranges ofcompound are 0.1 milligrams to 2 grams of active ingredient (moreusually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to10 milligrams, e.g. 0.1 milligrams to 2 milligrams of activeingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 18-1

The compounds of Examples 1-1 to 18-1 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 3. The starting materials for each of theExamples are listed in Table 2

TABLE 1 Example compounds

Example 1-1

Example 1-2

Example 2-1

Example 2-2

Example 3-1

Example 3-2

Example 3-3

Example 3-4

Example 3-5

Example 4-1

Example 4-2

Example 4-3

Example 4-4

Example 4-5

Example 5-1

Example 5-2

Example 6-1

Example 6-2

Example 7-1

Example 7-2

Example 7-3

Example 7-4

Example 7-5

Example 7-6

Example 7-7

Example 7-8

Example 8-1

Example 8-2

Example 8-3

Example 8-4

Example 8-5

Example 8-6

Example 8-7

Example 8-8

Example 8-9

Example 8-10

Example 8-11

Example 8-12

Example 8-13

Example 8-14

Example 8-15

Example 8-16

Example 8-17

Example 8-18

Example 9-1

Example 9-2

Example 9-3

Example 9-4

Example 9-5

Example 9-6

Example 9-7

Example 10-1

Example 11-1

Example 11-2

Example 11-3

Example 11-4

Example 11-5

Example 11-6

Example 11-7

Example 11-8

Example 12-1

Example 12-2

Example 12-3

Example 12-4

Example 13-1

Example 14-1

Example 15-1

Example 15-2

Example 16-1

Example 16-2

Example 16-3

Example 16-4

Example 16-5

Example 16-6

Example 16-7

Example 16-8

Example 16-9

Example 16-10

Example 16-11

Example 16-12

Example 16-13

Example 16-14

Example 17-1

Example 17-2

Example 17-3

Example 17-4

Example 17-5

Example 17-6

Example 17-7

Example 17-8

Example 17-9

Example 17-10

Example 17-11

Example 17-12

Example 17-13

Example 17-14

Example 17-15

Example 17-16

Example 17-17

Example 18-1

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker orJeol instrument. Chemical shift values are expressed in parts permillion (ppm), i.e. (δ)-values. The following abbreviations are used forthe multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 60-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions.Column chromatography performed using ‘basic silica’ refers to the useof Biotage® KP-NH silica gel. Column chromatography performed underreversed phase conditions using ‘C18 silica’ refers to the use ofBiotage® KP-C18 silica gel. TLC for monitoring reactions refers to TLCrun using the specified mobile phase and the Silica gel F254 as astationary phase from Merck. Microwave-mediated reactions were performedin Biotage Initiator or CEM Discover microwave reactors.

LCMS Analysis

LCMS analysis of compounds was performed under electrospray conditionsusing the instruments and methods given in the tables below:

Mass System Instrument Name LC Detector Detector 1 Waters Acquity HClass Photo Diode Array SQ Detector 2 Shimadzu Nexera Photo Diode ArrayLCMS-2020 3 Agilent 1290 RRLC Photo Diode Array Agilent 6120 4 HewlettPackard HP G1315A DAD Micromass 1100 ZQ 5 Agilent 1260 Infinity PhotoDiode Array Agilent LC 6120B

Method Solvent UV Mass Column Flow Rate Name System Column used GradientRange Range Temp.° C. mL/min A (A) 5 mM BEH C18 2.1 × 95:5 at 0.01 minup to 0.40 min, 65:35 at 200-400 nm 100-1200 amu Ambient 0.55 ammonium50 mm, 1.7 μm 0.80 min, 45:55 at 1.20 min, 0:100 at 2.50 acetate + 0.1%or equivalent min up to 3.30 min, 95:5 at 3.31 min up to formic acid in4.00 min water (B) 0.1% formic acid in acetonitrile B (A) 2 mM BEH C182.1 × 98:2 at 0.01 min up to 0.30 min, 50:50 at 200-400 nm 100-1200 amuAmbient 0.55 ammonium 50 mm, 1.7 μm 0.60 min, 25:75 at 1.10 min, 0:100at 2.00 acetate + 0.1% or equivalent min up to 2.70 min, 98:2 at 2.71min up to formic acid in 3.00 min water (B) 0.1% formic acid inacetonitrile C (A) 20 mM X-Bridge C18 100:0 at 0.01 min, 50:50 at 7.00min, 200-400 nm 60-1000 amu Ambient 1.00 ammonium 4.6 × 150 mm, 5 0:100at 9.00 min upto 11.00 min, 100:0 acetate in water μm or equivalent at11.01 min up to 12.00 min (B) methanol D (A) 0.1% X-Bridge C18 95:5 at0.01 min, 10:90 at 5.00 min, 5:95 200-400 nm 60-1000 amu Ambient 1.00ammonia in 4.6 × 50 mm, at 5.80 min up to 7.20 min, 95:5 at 7.21 water3.5 μm or min up to 10.00 min (B) 0.1% equivalent ammonia inacetonitrile E (A) 5 mM X-Bridge C18 95:5 at 0.01 min, 10:90 at 5.0 min& 5:95 200-400 nm 60-1000 amu Ambient 1.00 ammonium 4.6 × 50 mm, at 5.80min till 7.20 min, 95:5 at 7.21 min bicarbonate in 3.5 μm or up to 10.0min water equivalent (B) acetonitrile F (A) 2.5 L water + Gemini-NXC-18, 98:2 at 0.00 min up to 0.10 min, 5:95 at 230-400 nm 130-800 amu 451.50 2.5 mL 28% 2.0 × 30 2.50 min up to 3.50 min ammonia mm, 3 μmsolution in water (B) 2.5 L acetonitrile + 135 mL water + 2.5 mL 28%ammonia solution in water G (A) 2.5 L water + Gemini-NX C-18, 98:2 at0.00 min up to 0.10 min, 5:95 at 230-400 nm 130-800 amu 45 1.50 2.5 mL28% 2.0 × 30 8.40 min up to 10.00 min ammonia mm, 3 μm solution in waterB) 2.5 L acetonitrile + 135 mL water + 2.5 mL 28% ammonia solution inwater H (A) 2.5 L water + Gemini-NX C-18, 95:5 at 0.00 min, 5:95 at 2.00min up to 190-400 nm 150-800 amu 40 1.50 2.5 mL 28% 2.0 × 30 2.50 min,95:5 at 2.60 min up to 3.0 min ammonia mm, 3 μm solution in water (B)2.5 L acetonitrile + 130 mL water + 2.5 mL 28% ammonia solution in waterI (A) 5 mM BEH C18 2.1 × 98:2 at 0.01 min up to 0.5 min, 10:90 at200-400 nm 60-1000 amu Ambient 0.45 Ammonium 50 mm, 1.7 μm 5.0 min, 5:95at 6.0 min up to 7.0 min, acetate & 0.1% or equivalent 98:2 at 7.01 minup to 8.0 min formic acid in water (B) 0.1% formic acid in acetonitrileJ (A) 20 mM X-Bridge C18 90:10 at 0.01 min, 10:90 at 5.00 min, 200-400nm 60-1000 amu Ambient 1.00 ammonium 4.6 × 150 mm, 5 0:100 at 7.00 minupto 11.00 min, 90:10 acetate in water μm or equivalent at 11.01 min upto 12.00 min (B) Methanol K (A) 0.1% YMC Triart C18 95:5 at 0.01 min,50:50 at 5.0 min,10:90 200-400 nm 100-1200 amu Ambient 1.00trifluoroacetic (4.6 × 150 mm), 5 at 8.0 min, 0:100 at 10.0 min upto11.0 acid in water μm or equivalent min, 95:5 at 11.01 min up to 12.0min (B) 100% acetonitrile

LCMS data in the experimental section and Tables 2 and 3 are given inthe format: (Instrument system, Method): Mass ion, retention time, UVdetection wavelength.

Compound Purification

Final purification of compounds was performed by preparative reversedphase HPLC, chiral HPLC or chiral SFC using the instruments and methodsdetailed below where data is given in the following format: Purificationtechnique: [phase (column description, column length×internal diameter,particle size), solvent flow-rate, gradient—given as % of mobile phase Bin mobile phase A (over time), mobile phase (A), mobile phase (B)].

Preparative HPLC purification:

Shimadzu LC-20AP binary system with SPD-20A UV detector Gilson semipreparative HPLC system with 321 pump, GX-271 liquid handler and Gilson171 DAD controlled with Gilson Trilution software Chiral HPLCpurification:

Shimadzu LC-20AP binary system with SPD-20A UV detector Chiral SFCpurification:

Waters SFC 200

Purification Method A

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 15 mL/min,gradient 0%-50% (over 18 min), 100% (over 2 min), 100%-0% (over 3 min),mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B):acetonitrile:methanol (50:50)].

Purification Method B

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 0%-15% (over 21 min), 15%-15% (over 3 min), 100% (over 2 min),100%-0% (over 2 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1%ammonia in water, (B): 100% acetonitrile].

Purification Method C

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 40%-60% (over 8.7 min), 60% (over 0.5 min), 60%-100% (over 0.2min), 100% (over 1 min), 100%-40% (over 0.2 min), 40% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method D

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×50 mm, 5 μm), 65 mL/min,gradient 0%-25% (over 30 min), 25%-25% (over 1 min), 100% (over 2 min),100%-0% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1%ammonia in water, (B): 100% acetonitrile].

Purification Method E

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 60%-100% (over 8.7 min), 100% (over 1.7 min), 100%-60% (over0.2 min), 60% (over 0.9 min), mobile phase (A): 2.5 L of water+5 mL of28% ammonia solution in water, (B): 100% acetonitrile].

Purification Method F

Prep HPLC: [Reversed Phase (Kromasil eternity C-18, 250×21.2 mm, 5 μm),15 mL/min, gradient 7%-20% (over 27 min), 100% (over 2 min), 100%-7%(over 3 min), mobile phase (A): 0.1% trifluoroacetic acid in water, (B):100% acetonitrile].

Purification Method G

Prep HPLC: [Reversed Phase (X-BRIDGE C-8, 150×19 mm, 5 μm), 16 mL/min,gradient 0%-25% (over 20 min), 25%-25% (over 3 min), 100% (over 2 min),100%-0% (over 5 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1%ammonia in water, (B): 100% acetonitrile].

Purification Method H

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 40%-70% (over 8.7 min), 70% (over 0.5 min), 70%-100% (over 0.2min), 100% (over 1 min), 100%-40% (over 0.2 min), 40% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method I

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 5%-95% (over 8.7 min), 95% (over 0.5 min), 95%-100% (over 0.2min), 100% (over 1 min), 100%-5% (over 0.2 min), 5% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method J

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 5%-35% (over 8.7 min), 35% (over 0.5 min), 35%-100% (over 0.2min), 100% (over 1 min), 100%-5% (over 0.2 min), 5% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Purification Method K

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 60%-100% (over 8.7 min), 100% (over 1.7 min), 100%-60% (over0.2 min), 60% (over 0.9 min), mobile phase (A): 2.5 L of water+5 mL of28% ammonia solution in water, (B): 100% acetonitrile].

Purification Method L

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 250×19 mm, 5 μm), 10 mL/min,gradient 0%-20% (over 30 min), 20%-20% (over 9 min), 100% (over 3 min),100%-0% (over 8 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1%ammonia in water, (B): 100% acetonitrile].

Purification Method M

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 13 mL/min,gradient 0%-35% (over 18 min), 100% (over 3 min), 100%-0% (over 4 min),mobile phase (A): 5 mM ammonium bicarbonate+0.1% ammonia in water, (B):100% acetonitrile].

Purification Method N

Chiral HPLC: [Normal Phase (CHIRALPAK IG, 250×21 mm, 5 μm), 18 mL/min,Isocratic (A:B) 70:30 (over 40 min), mobile phase (A): 0.1% diethylaminein hexane, (B): 0.1% diethylamine in isopropanol:methanol (50:50)].

Purification Method O

Prep HPLC: [Reversed Phase (X-BRIDGE C-18, 150×19 mm, 5 μm), 15 mL/min,gradient 10%-35% (over 20 min), 35% (over 3 min), 100% (over 2 min),100%-10% (over 3 min), mobile phase (A): 5 mM ammonium bicarbonate+0.1%ammonia in water, (B): acetonitrile:methanol (1:1)].

Purification Method P

SFC: [(CHIRALPAK IC, 250×21 mm, 5 μm), 80 mL/min, Isocratic (A:B) 65:35(over 23 min), mobile phase (A): 100% liquid CO₂, (B): 0.1% diethylaminein isopropanol:acetonitrile (50:50)].

Purification Method Q

Prep HPLC: [Reversed Phase (Gemini-NX C-18, 100×30 mm, 5 μm), 30 mL/min,gradient 30%-60% (over 8.7 min), 60% (over 0.5 min), 60%-100% (over 0.2min), 100% (over 1 min), 100%-30% (over 0.2 min), 30% (over 0.9 min),mobile phase (A): 2.5 L of water+5 mL of 28% ammonia solution in water,(B): 100% acetonitrile].

Abbreviations

CDI=carbonyldiimidazole

DAST=diethylaminosulfur trifluoride

DCM=dichloromethane

DIPEA=N,N-diisopropylethylamine

ESI=electro spray ionisation

EtOAc=ethyl acetate

h=hour(s)

H₂O=water

HCl=hydrogen chloride, hydrochloric acid

HPLC=high performance liquid chromatography

IPA=propan-2-ol

LC=liquid chromatography

MeCN=acetonitrile

MeOH=methanol

min(s)=minute(s)

MS=mass spectrometry

nm=nanometre(s)

NMR=nuclear magnetic resonance

POCl₃=phosphorus oxychloride

RT=room temperature

sat.=saturated

SFC=supercritical fluid chromatography

TEA=triethylamine

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

Synthesis of Intermediates Route 1 Typical Procedure for the Preparationof Pyrazoles, as Exemplified by the Preparation of Intermediate 12,5-bromo-3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbaldehyde(Intermediate 11) (800 mg, 2.60 mmol) dissolved in DCM (8.7 mL) andcooled to 0° C. was added diethylaminosulfur trifluoride (0.86 mL, 6.51mmol) dropwise. The reaction mixture was then stirred at 0° C. for 23hours, allowing it to slowly warm to RT. The reaction mixture was thenquenched at 0° C. by the addition of saturated sodium bicarbonatesolution and the resulting mixture was extracted using DCM (×2). Thecombined organic phases were filtered through a phase separator andconcentrated under reduced pressure. The crude product was then purifiedusing column chromatography (silica, 0-50% dichloromethane in petroleumether) to give5-bromo-3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(Intermediate 12) (716 mg, 84%).

The data for Intermediate 12 are in Table 2.

Route 2 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 15,3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

Ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 14)(1.50 g, 7.21 mmol) was dissolved in MeOH (15 mL) and aqueous NaOH (2 M,10 mL) was added dropwise. The resulting reaction mixture was stirred at70° C. for 14 h, then concentrated in-vacuo. The residue was dissolvedin water (5 mL), acidified with aqueous HCl (1 M) to pH=2-3 andextracted with ethyl acetate (3×15 mL). The combined organic layers weredried (Na₂SO₄) and the solvent was removed in-vacuo to give the crudeproduct which was triturated with pentane (decanting off the solvent)and dried under high vacuum to give3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Intermediate 15)(1.30 g, 100%) as a solid.

The data for Intermediate 15 are in Table 2.

Route 3 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 22,4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Sodium hydride suspension in mineral oil (60%, 624 mg, 15.6 mmol) wasadded in small increments to a solution of 4-ethyl-1H-pyrazole(Intermediate 20) (1.0 g, 10.4 mmol) in THF (5.2 mL), pre-cooled to 0°C. The reaction mixture was stirred at 0° C. for 45 min before thedropwise addition of (2-(chloromethoxy)ethyl)trimethylsilane(Intermediate 21) (2.0 mL, 11.4 mmol). The reaction mixture was stirredat room temperature for 18 h, then quenched at 0° C. by the addition ofwater and extracted into ethyl acetate. The aqueous layer was furtherextracted using ethyl acetate (×2), and the combined organic phases werewashed with brine, filtered through a phase separator and concentratedunder reduced pressure. The residue was purified using columnchromatography (silica, 0-10% ethyl acetate in petroleum ether) to give4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, (Intermediate22) (1.50 g, 63%).

The data for Intermediate 22 are in Table 2.

Route 4 Typical Procedure for the Preparation of Pyrimidines, asExemplified by the Preparation of Intermediate 26, tert-butyl(R)-(1-(6-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate

A mixture of 4,6-dichloropyrimidin-2-amine (Intermediate 1) (18.54 g,113 mmol), hexane-2,5-dione (Intermediate 25) (26.5 mL, 226 mmol) andp-toluenesulfonic acid monohydrate (215 mg, 1.13 mmol) in dry toluene(500 mL) was heated at reflux under Dean & Stark conditions for 17 h(overnight). The reaction mixture was cooled to room temperature andwashed with sat. sodium bicarbonate solution. The aqueous layer wasextracted with EtOAc, and the combined organic phases were washed withwater and brine, filtered through a phase separator and concentrated.The residue was then filtered through a plug of silica, washing with DCMand concentrated to give4,6-dichloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidine (24.9 g, 91%).

1H NMR (400 MHz, Chloroform-d) δ 7.19 (s, 1H), 5.91 (s, 2H), 2.42 (s,6H).

To a solution of 4,6-dichloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidine(3.0 g, 12.4 mmol) dissolved in DCM (20 mL) was addedN,N-diisopropylethylamine (6.48 mL, 37.2 mmol) followed by tert-butyl(R)-methyl(pyrrolidin-3-yl)carbamate (Intermediate 3) (2.61 g, 13.0mmol) dissolved in DCM (20 mL). The reaction mixture was stirred at roomtemperature for 20 h, then quenched by the addition of aqueous HCl (1 M)and extracted using DCM (×2). The combined organic phases were filteredthrough a phase separator and concentrated under reduced pressure. Theresidue was then purified using column chromatography (silica, 0-25%ethyl acetate in petroleum ether) to give tert-butyl(R)-(1-(6-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 26) (3.87 g, 77%).

The data for Intermediate 26 are in Table 2.

Route 5 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 31,1,5-dimethyl-1H-pyrazole-3-carboxylic acid

Ethyl 5-methyl-1H-pyrazole-3-carboxylate (Intermediate 30) (2.0 g, 0.01mol) was dissolved in DMF (15 mL) and sodium hydride suspension inmineral oil (60%, 1.5 g, 0.03 mol) was added portion-wise under nitrogenat 0° C. The mixture was stirred for 1 h, then methyl iodide (3.6 g,0.02 mol) was added dropwise under nitrogen and the resulting mixturewas stirred at room temperature for 16 h. The reaction mixture wasconcentrated, and the residue was partitioned between H₂O (25 mL) andEtOAc (15 mL). The aqueous layer was further extracted with EtOAc (3×15mL) and the combined organic layers were dried (Na₂SO₄) and the solventwas removed in-vacuo. The residue was purified by column chromatography(Normal-Phase 60-120 mesh silica gel, 0 to 3% MeOH in DCM) to give ethyl1,5-dimethyl-1H-pyrazole-3-carboxylate (2.0 g, 96%) as a gum.

LCMS (System 1, Method B): m/z 169 (M+H)⁺ (ESI +ve), at 1.42 min, 230nm.

Ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate (2.0 g, 0.01 mol), andLiOH.H₂O (1.4 g, 0.03 mol) were taken into THF (5 mL) and water (2 mL)and stirred at 0° C. for 1 h. The reaction mixture was partitionedbetween H₂O (25 mL) and EtOAc (15 mL), and the organic extract wasdiscarded. The aqueous layer was acidified to pH 1-2 using aqueous HCl(1 M) and the resulting mixture was re-extracted with EtOAc (3×15 mL).The combined extracts were dried (Na₂SO₄) and the solvent was removedin-vacuo to give 1,5-dimethyl-1H-pyrazole-3-carboxylic acid(Intermediate 31) (1.3 g, 81%) as a gum.

The data for Intermediate 31 are in Table 2.

Route 6 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 36,1-(difluoromethyl)-4-methyl-1H-pyrazole-3-carboxylic acid

Ethyl 4-methyl-1H-pyrazole-3-carboxylate (Intermediate 33) (1.0 g, 6.49mmol) was dissolved in DMF:H₂O (9.0 mL:1.0 mL) and K₂CO₃ (3.58 g, 25.9mmol) and sodium 2-chloro-2,2-difluoroacetate (Intermediate 35) (3.94 g,25.9 mmol) were added at 0° C. and then the mixture was heated at 130°C. for 20 min. The reaction mixture was cooled to RT and ice-cold waterwas added. The aqueous layer was extracted with EtOAc (3×50 mL) and thecombined organic layer was washed with brine solution, dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (Normal-Phase 60-120 mesh silica gel, 25% EtOAc inhexanes) to give ethyl1-(difluoromethyl)-4-methyl-1H-pyrazole-3-carboxylate (325 mg, 25%) as asolid.

LCMS (System 3, Method D): m/z 205 (M+H)⁺ (ESI +ve), at 3.77 min, 202nm.

Ethyl 1-(difluoromethyl)-4-methyl-1H-pyrazole-3-carboxylate (325 mg,1.59 mmol) was dissolved in MeOH:H₂O (9:1.10 mL), LiOH.H₂O (334 mg, 7.96mol) was added 0° C. and the reaction mixture was stirred at RTovernight. The solvent was removed under reduced pressure and ice-coldwater was added. The mixture was neutralized with dilute aqueous HCl andthe aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic extracts were washed with brine solution, dried over Na₂SO₄,filtered and concentrated to give1-(difluoromethyl)-4-methyl-1H-pyrazole-3-carboxylic acid (Intermediate36) (251 mg, 96%) as a solid.

The data for Intermediate 36 are in Table 2.

Route 7 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 63, ethyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

tert-Butyl 3-oxopiperidine-1-carboxylate (Intermediate 60) (1.30 g, 6.53mmol) was dissolved in methanol (20 mL), and NaBH₄ (750 mg, 19.6 mmol)at was added portion-wise at 0° C. The resulting mixture was stirred atroom temperature for 3 h, then partitioned between H₂O (50 mL) and EtOAc(20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL),and the combined organic layers were dried (Na₂SO₄) and the solvent wasremoved in-vacuo to give crude product. The residue was purified bycolumn chromatography (Normal-Phase 60-120 mesh silica gel, 0 to 50%EtOAc in hexanes) to give tert-butyl 3-hydroxypiperidine-1-carboxylate(1.00 g, 76%) as a solid.

LCMS (System 1, Method B): m/z 202 (M+H)⁺ (ESI +ve), at 1.50 min, 202nm.

tert-Butyl 3-hydroxypiperidine-1-carboxylate (1.00 g, 4.98 mmol) and TEA(2.1 mL, 14.9 mmol) were dissolved in DCM (15 mL) at 0° C., methanesulfonyl chloride (850 mg, 7.45 mmol) was added dropwise at 0° C. andthe resulting mixture was stirred at room temperature for 3 h. Thereaction mixture was then partitioned between H₂O (50 mL) and DCM (20mL), and the aqueous layer was further extracted with DCM (2×20 mL). Thecombined organic layers were dried (Na₂SO₄) and the solvent was removedin-vacuo. The residue was purified by column chromatography(Normal-Phase 60-120 mesh silica gel, 0 to 30% EtOAc in hexanes) to givetert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.03 g, 94%)as a gum.

LCMS (System 1, Method B): m/z 280 (M+H)⁺ (ESI +ve), at 1.61 min, 202nm.

4-Bromo-1H-pyrazole (Intermediate 61) (526 mg, 3.58 mmol) was dissolvedin DMF (10 mL), sodium hydride suspension in mineral oil (60%, 260 mg,6.45 mmol) was added at 0° C. and the resulting mixture was stirred for30 min. tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.00g, 3.58 mmol) as a solution in DMF (5 mL) was added dropwise at 0° C.and the mixture was stirred at 120° C. for 1 h using microwave heating.The reaction mixture was partitioned between H₂O (50 mL) and EtOAc (20mL) and the aqueous layer was further extracted with EtOAc (2×20 mL).The combined organic layers were dried (Na₂SO₄) and the solvent wasremoved in-vacuo. The residue was purified by column chromatography(Normal-Phase 60-120 mesh silica gel, 0 to 3% MeOH in DCM) to givetert-butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.10 g,93%) as a gum.

LCMS (System 1, Method B): m/z 274/276 (M−56+H)⁺ (ESI +ve), at 1.82 min,230 nm.

tert-Butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (700 mg,2.12 mmol) was dissolved in HCl solution in 1,4-dioxane (4 M, 15 mL) at0° C. and the resulting mixture was stirred at room temperature for 3 h.The reaction mixture was concentrated and the residue then trituratedwith diethyl ether (2×10 mL) to give3-(4-bromo-1H-pyrazol-1-yl)piperidine hydrochloride salt (400 mg, 71%)as a solid.

LCMS (System 2, Method E): m/z 230/232 (M+H)⁺ (ESI +ve), at 2.54 min,230 nm.

3-(4-Bromo-1H-pyrazol-1-yl)piperidine hydrochloride salt (500 mg, 2.17mmol) and TEA (0.90 mL, 6.52 mmol) were dissolved in DCM (15 mL) at 0°C. and ethyl chloroformate (Intermediate 62) (350 mg, 3.26 mmol) wasadded dropwise at 0° C. The resulting mixture was stirred for 3 h atroom temperature, then partitioned between H₂O (20 mL) and DCM (10 mL).The aqueous layer was further extracted with DCM (2×10 mL) and thecombined organic layers were dried (Na₂SO₄) and the solvent was removedin-vacuo. The residue was purified by column chromatography(Normal-Phase 60-120 mesh silica gel, 0 to 2% MeOH in DCM) to give ethyl3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (400 mg, 61%) as agum.

LCMS (System 1, Method B): m/z 302/304 (M+H)⁺ (ESI +ve), at 1.67 min,233 nm.

Ethyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (400 mg, 1.32mmol), bis(pinacolato)diboron (Intermediate 8) (400 mg, 1.59 mmol) andpotassium acetate (450 mg, 4.63 mmol) were dissolved in DMSO (5 mL)under nitrogen and the resulting solution was degassed for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane complex (CAS: 95464-05-4) (378 mg, 0.46 mmol) was addedand the mixture was heated at 90° C. for 16 h. The reaction mixture wasthen partitioned between H₂O (25 mL) and EtOAc (15 mL), and the aqueouslayer was further extracted with EtOAc (2×15 mL). The combined organiclayers were dried (Na₂SO₄) and the solvent was removed in-vacuo. Theresidue was purified by column chromatography (Normal-Phase 60-120 meshsilica gel, 0 to 2% MeOH in DCM) to give ethyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Intermediate 63) (200 mg, 43%) as a gum.

The data for Intermediate 63 are in Table 2.

Route 8 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 71,4-bromo-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

4-Bromo-3-ethyl-1H-pyrazole (Intermediate 69) (500 mg, 2.8 mmol) wasdissolved in 1,2-dichloroethane (5 mL) and 3,4-dihydropyran(Intermediate 70) (482 mg, 5.7 mmol) was added. Trifluoroacetic acid(2-3 drops) was then added and the resulting mixture was stirred at RTfor 24 h. The solvent was evaporated, and the residue was partitionedbetween ethyl acetate (25 mL) and water (15 ml). The organic layer wasseparated, dried (Na₂SO₄) and evaporated under reduced pressure. Theresidue was purified by column chromatography (silica gel 60-120 mesh,0-20% ethyl acetate in hexane) to give4-bromo-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Intermediate71) (700 mg, 97%) as a gum.

The data for Intermediate 71 are in Table 2.

Route 9 Typical Procedure for the Preparation of Pyrrolidines, asExemplified by the Preparation of Intermediate 88, benzylmethyl(3-methylpyrrolidin-3-yl)carbamate hydrochloride

tert-Butyl 3-amino-3-methylpyrrolidine-1-carboxylate (Intermediate 86)(600 mg, 3.00 mmol) was dissolved in THF (8 mL) and a solution of NaHCO₃(504 mg, 6.00 mmol) in water (8 mL) was added. The mixture was cooled to0° C. and benzyl chloroformate (Intermediate 87) as a solution intoluene (50%, 1.1 mL, 3.30 mmol) was added, and the resulting mixturewas stirred at 25° C. for 2 h. The reaction mixture was then partitionedbetween H₂O (30 mL) and ethyl acetate (20 mL), and the aqueous layer wasfurther extracted with ethyl acetate (2×20 mL). The combined organiclayers were dried (Na₂SO₄) and the solvent was removed in-vacuo. Theresidue was purified by triturating with pentane to give tert-butyl3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (900mg, 90%) as a gum.

LCMS (System 3, Method D): m/z 333 (M−H)⁻ (ESI −ve), at 4.68 min, 202nm.

tert-Butyl3-(((benzyloxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (900mg, 2.69 mmol) was dissolved in THF (15 mL) and the solution was cooledto 0° C. Sodium hydride suspension in mineral oil (60%, 323 mg, 8.08mmol) was added and the reaction mixture was stirred at 0° C. for 30min. Methyl iodide (573 mg, 4.04 mmol) was added at 0° C. and theresulting reaction mixture was stirred at 25° C. for 4 h. The mixturewas then partitioned between H₂O (40 mL) and EtOAc (25 mL), and theaqueous layer was further extracted with EtOAc (2×25 mL). The combinedorganic layers were dried (Na₂SO₄) and the solvent was removed in-vacuoto give the crude product, which was purified by triturating withpentane to give tert-butyl3-(((benzyloxy)carbonyl)(methyl)amino)-3-methylpyrrolidine-1-carboxylate(910 mg, 97%) as a gum.

LCMS (System 3, Method D): m/z 349 (M+H)⁺ (ESI +ve), at 5.05 min, 202nm.

tert-Butyl3-(((benzyloxy)carbonyl)(methyl)amino)-3-methylpyrrolidine-1-carboxylate(900 mg, 2.59 mmol) was dissolved 1,4-dioxane (5 mL) and cooled to 0° C.HCl solution in 1,4-dioxane (4 M, 10 mL) was added under a nitrogenatmosphere and the resulting mixture was stirred at room temperature for6 h. The reaction mixture was concentrated and the crude product saltwas purified by trituration with pentane (2×2 mL) to give benzylmethyl(3-methylpyrrolidin-3-yl)carbamate hydrochloride (Intermediate 88)(640 mg, 100%) as a gum.

The data for Intermediate 88 are in Table 2.

Route 10 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 111,4-(difluoromethyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylic acid

Ethyl 4-formyl-1H-pyrazole-3-carboxylate (Intermediate 109) (1 g, 5.95mmol) was dissolved in DMF (10 mL), followed by the addition of1-(chloromethyl)-4-methoxybenzene (Intermediate 110) (1.02 g, 6.54 mmol)at RT. To this was then added potassium carbonate (904 mg, 6.54 mmol)and potassium iodide (10 mg) and the reaction stirred at 80° C. for 16h. The reaction mixture was partitioned between H₂O (250 mL) and EtOAc(500 mL) and the aqueous layer was further extracted with EtOAc (2×150mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting product was purified by columnchromatography (Normal-Phase 60-120 mesh silica gel, 0 to 50% EtOAc inHexane) to give ethyl4-formyl-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (1.0 g, 58%).

LCMS (System 1, Method B): m/z 289 (M+H)⁺ (ESI +ve), at 1.61 min, 275nm.

Ethyl 4-formyl-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (0.8 g,2.77 mmol) was dissolved in DCM (8 mL). The reaction mixture was cooledto −70° C. and to this was then added dropwise diethylaminosulfurtrifluoride (1.11 g, 6.94 mmol). The reaction mixture was then allowedto warm at RT and stirred for 16 h. The reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (250 mL) and EtOAc (500 mL). Theaqueous layer was further extracted with EtOAc (2×150 mL) and thecombined organic layers were dried (Na₂SO₄), filtered and concentratedin vacuo. The resulting product was purified by column chromatography(Normal-Phase 60-120 mess silica gel, 0 to 18% EtOAc in Hexane) to giveethyl 4-(difluoromethyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate(0.8 g, 93%).

LCMS (System 1, Method B): m/z 311 (M+H)⁺ (ESI +ve), at 1.71 min, 230nm. Ethyl4-(difluoromethyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (0.8 g,2.58 mmol) was dissolved in THF (4 mL) and MeOH (4 mL). To this addedaqueous NaOH (2M, 6.45 mL, 12.9 mmol) and stirred at RT for 16 h. Theorganic solvent was removed in vacuo and the resulting solution wascooled to 10° C. The reaction mixture was acidified to pH 2 usingaqueous 6M HCl and the resulting precipitate was collected by filtrationand dried in vacuo to give4-(difluoromethyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylic acid(Intermediate 111) (0.7 g, 96%).

The data for Intermediate 111 are in Table 2.

Route 11 Typical Procedure for the Partial Deprotection of Pyrimidines,as Exemplified by the Preparation of Intermediate 118, tert-butyl(R)-(1-(2-amino-6-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate

A mixture of tert-butyl(R)-(1-(2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 117) (226 mg, 0.39 mmol), hydroxylamine hydrochloride (268mg, 3.86 mmol) and triethylamine (0.06 mL, 0.42 mmol) in ethanol (8 mL)and water (4 mL) was heated at 100° C. overnight. The reaction mixturewas diluted with water and extracted with EtOAc (×3). The combinedorganic extracts were washed with brine, passed through a phaseseparator and concentrated to give tert-butyl(R)-(1-(2-amino-6-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 118) (189 mg, 96%) as a gum.

The data for Intermediate 118 are in Table 2.

Route 12 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 121,4-(methylthio)-1H-pyrazole-3-carboxylic acid

Ethyl 4-amino-1H-pyrazole-3-carboxylate (Intermediate 120) (4.00 g, 2.57mmol) was dissolved in ACN (40.0 mL), then isopentyl nitrite (10.39 mL)was added followed by addition of dimethyl disulfide (6.87 mL, 7.73mmol) drop wise under nitrogen at 0° C. and stirred for 1 hr. Then thereaction was heated at 80° C. with stirring for 16 hrs. Once completeconsumption of starting material was achieved, the reaction mixture wascooled to about 15° C. and partitioned between H₂O (100 mL) and EtOAc(50 mL), aqueous layer was further extracted with EtOAc (2×50 mL); allorganic layers combined, dried (Na₂SO₄) and solvent was removed in vacuoto give crude product. Crude product was purified by columnchromatography silica gel (60-120 mesh) and gradient 0 to 50% EtOAc inhexanes. Distilled out solvent to give ethyl4-(methylthio)-1H-pyrazole-3-carboxylate (3.0 g, 62.5%) as a yellow gum.

LCMS (System 1, Method B): m/z 187 (M+H)⁺ (ESI +ve), at 1.39 min, 230nm.

Ethyl 4-(methylthio)-1H-pyrazole-3-carboxylate (3.5 g, 1.87 mmol) wasdissolved methanol (25 mL), followed by addition of 2N NaOH aqueoussolution (28 mL, 5.63 mmol) drop wise and stirred for 16 hr. at roomtemperature. The reaction mixture was concentrated, diluted with icecold water (small quantity), acidified with diluted HCl and theresulting suspension was stirred for further 20-30 min. Solid compoundwas collected by filtration. The solid was dry under reduce pressure togive 4-(methylthio)-1H-pyrazole-3-carboxylic acid (2.5 g, 84.17%) as awhite solid.

The data for Intermediate 121 are in Table 2.

Route 13 Typical Procedure for the Preparation of Pyrazoles, asExemplified by the Preparation of Intermediate 127,4-methoxy-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylicacid

Ethyl 5-methyl-1H-pyrazole-3-carboxylate (Intermediate 30) (4.00 g, 25.9mmol), was dissolved in DCM (100 mL), followed by addition of N-Iodosuccinimide (7.09 g, 31.1 mmol) portionwise and stirred at roomtemperature for 16 hrs. The reaction mixture was partitioned between H₂O(60 mL) and EtOAc (30 mL), aqueous layer was further extracted withEtOAc (2×30 mL); combined organic layers combined, dried (Na₂SO₄) andsolvent was removed in vacuum to give crude product. The crude productwas purified by column chromatography (60-120 mesh silica gel, 0 to 4%methanol in DCM) to ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate(6.80 g, 93.53%) as a colorless gum.

LCMS (System 1, Method B): m/z 281 (M+H)⁺ (ESI +ve), at 1.49 min, 229 nm

Ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate (3.10 g, 11.1 mmol) and3,4-dihydro-2H-pyran (1.39 g, 16.6 mmol) were dissolved in DCM (50.0mL), followed by addition of Pyridinium p-toluene sulfonate (0.28 g,1.11 mmol) portion wise and stirred over 16 hrs. at 40° C. The reactionmixture was partitioned between H₂O (50 mL) and EtOAc (20 mL), aqueouslayer was further extracted with EtOAc (2×20 mL), all organic layerscombined, dried (Na₂SO₄) and solvent was removed in vacuum to give crudeproduct. The crude product was purified by column chromatography (60-120mesh silica gel, 0 to 2% methanol in DCM) to give ethyl4-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate(3.20 g, 79.40%) as a white solid.

LCMS (System 1, Method B): m/z 365 (M+H)⁺ (ESI +ve), at 1.73 min, 235 nm

Ethyl4-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate(3.20 g, 8.80 mmol) and CuI (0.50 g, 2.64 mmol) were added to freshlyprepared sodium methoxide solution (30.0 mL) and stirred at roomtemperature for 16 hrs. at 80° C. The reaction mixture was filteredthrough celite and the filtrate concentrated. The concentrated reactionmixture was dumped in to water (20 mL) and acidify by addition of 1N HClsolution (pH˜4.0) and extracted with 10% MeOH in DCM (3×30 mL), allorganic layers combined, dried (Na₂SO₄) and solvent was removed in vacuoto give4-methoxy-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylicacid (2.45 g, 100% w/w) as a yellow gum.

The data for Intermediate 127 are in Table 2.

General Synthetic Procedures Route A Typical Procedure for thePreparation of Pyrimidines as Exemplified by the Preparation of Example1-1,(R)-4-(3-(methylamino)pyrrolidin-1-yl)-6-(1H-pyrazol-5-yl)pyrimidin-2-amine

4,6-Dichloropyrimidin-2-amine (Intermediate 1) (250 mg, 1.52 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 2) (354 mg, 1.82 mmol) and K₃PO₄ (970 mg, 4.50 mmol) weredissolved in 1,4-dioxane (5 mL) and water (0.5 mL) under nitrogen anddegassed for 20 min. Then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane complex (CAS: 95464-05-4) (124 mg, 0.15 mmol) was addedunder a nitrogen atmosphere, and the resulting mixture was stirred at90° C. for 16 h. The reaction mixture was partitioned between H₂O (25mL) and EtOAc (15 mL), and the aqueous layer was further extracted withEtOAc (2×15 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo to give the crude product, which waspurified by column chromatography (Normal-Phase 60-120 mesh silica gel,0 to 6% MeOH in DCM) to give4-chloro-6-(1H-pyrazol-5-yl)pyrimidin-2-amine (75 mg, 25%) as a solid.

LCMS (System 1, Method B): m/z 196 (M+H)⁺ (ESI +ve), at 1.38 min, 240nm.

4-Chloro-6-(1H-pyrazol-5-yl)pyrimidin-2-amine (75 mg, 0.38 mmol) andtert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (Intermediate 3) (76 mg,0.38 mmol) were dissolved in triethylamine (3 mL) and stirred at 90° C.for 16 h. The reaction mixture was concentrated and then partitionedbetween H₂O (25 mL) and EtOAc (15 mL). The aqueous layer was furtherextracted with EtOAc (2×15 mL), and the combined organic layers weredried (Na₂SO₄) and solvent was removed in-vacuo to give the crudeproduct, which was purified by column chromatography (Normal-Phase60-120 mesh silica gel, 0 to 3% MeOH in DCM) to give tert-butyl(R)-(1-(2-amino-6-(1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(75 mg, 54%) as a solid.

LCMS (System 1, Method B): m/z 360 (M+H)⁺ (ESI +ve), at 1.44 min, 220nm.

tert-Butyl(R)-(1-(2-amino-6-(1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(75 mg, 0.20 mmol) was dissolved in HCl solution in 1,4-dioxane (4 M, 2mL) under nitrogen at 0° C. and stirred for 3 h at room temperature. Thereaction mixture was concentrated and triturated with diethyl ether (2×5mL) to give the crude product, which was purified by purification MethodA to give(R)-4-(3-(methylamino)pyrrolidin-1-yl)-6-(1H-pyrazol-5-yl)pyrimidin-2-amine,Example 1-1 (21 mg, 39%) as a colorless gum.

The data for Example 1-1 are in Table 3.

Route B Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 1-2,(R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-aminedihydrochloride

4,6-Dichloropyrimidin-2-amine (Intermediate 1) (5.5 g, 33.5 mmol) andtert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (Intermediate 3) (7.3 g,40.2 mmol), were dissolved in triethylamine (13 mL) and the resultingsolution was stirred at 90° C. for 3 h. During the reaction process theproduct precipitated out and it was filtered off, washed with water anddried in-vacuo to give tert-butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (10.1 g, 92%) as an off-white solid.

The data for Intermediate 4 are in Table 2.

tert-Butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (150 mg, 0.46 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 5) (115 mg, 0.55 mmol) and K₂CO₃ (126 mg, 0.92 mmol) weredissolved in 1,4-dioxane (5 mL) and water (2 mL) under nitrogen anddegassed for 20 min. Tetrakis(triphenylphosphine)palladium (0) (CAS:95464-05-4) (26 mg, 0.02 mmol) was added under a nitrogen atmosphere andthe resulting mixture was stirred at 90° C. for 16 h. The reactionmixture was partitioned between H₂O (25 mL) and EtOAc (15 mL), and theaqueous layer was further extracted with EtOAc (2×15 mL). The combinedorganic layers were dried (Na₂SO₄) and the solvent was removed in-vacuoto give the crude product, which was purified by column chromatography(Normal-Phase 60-120 mesh silica gel, 0 to 3% MeOH in DCM) to givetert-butyl(R)-(1-(2-amino-6-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(100 mg, 58%) as a gum.

LCMS (System 1, Method A): m/z 374 (M+H)⁺ (ESI +ve), at 1.40 min, 296nm.

tert-Butyl(R)-(1-(2-amino-6-(1-methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(100 mg, 0.27 mmol) was dissolved in HCl solution in 1,4-dioxane (4 M, 4mL) under nitrogen and stirred at room temperature for 6 h. The reactionmixture was concentrated and then triturated with diethyl ether (2×10mL) to give(R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-aminedihydrochloride, Example 1-2 (59 mg, 81%) as a solid.

The data for Example 1-2 are in Table 3.

Route C Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 2-1,(R)-4-(1-methyl-1H-pyrazol-3-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

tert-Butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (150 mg, 0.45 mmol),1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 6) (114 mg, 0.54 mmol) and K₃PO₄ (291 mg, 0.13 mmol) weredissolved in 1,4-dioxane (12 mL) and water (3 mL) under nitrogen anddegassed for 20 min. Then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane complex (CAS: 95464-05-4) (37 mg, 0.04 mmol) was addedunder a nitrogen atmosphere and the resulting mixture was stirred at 90°C. for 16 h. The reaction mixture was partitioned between H₂O (40 mL)and EtOAc (25 mL), and the aqueous layer was further extracted withEtOAc (3×25 mL). The organic layers were combined, dried (Na₂SO₄) andthe solvent was removed in-vacuo to give the crude product, which waspurified by column chromatography (Normal-Phase activated alumina, 2% to4% MeOH in DCM) to give tert-butyl(R)-(1-(2-amino-6-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(169 mg, 99%) as a solid.

LCMS (System 2, Method E): m/z 374 (M+H)⁺ (ESI +ve), at 3.31 min, 254nm.

tert-butyl(R)-(1-(2-amino-6-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(169 mg, 0.45 mmol) was dissolved in a mixture of TFA (2 mL) and DCM (4mL) under nitrogen and stirred at room temperature for 2 h. The reactionmixture was concentrated and then triturated with pentane (2×2 mL) togive the crude product, which was purified by purification Method B togive(R)-4-(1-methyl-1H-pyrazol-3-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 2-1 (94 mg, 76%) as a solid.

The data for Example 2-1 are in Table 3.

Route D Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 2-2,(R)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-aminedihydrochloride

A mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (CAS: 95464-05-4) (61 mg, 0.08 mmol),bis(pinacolato)diboron (Intermediate 8) (267 mg, 1.05 mmol),3-bromo-1-(difluoromethyl)-1H-pyrazole (Intermediate 7) (148 mg, 0.75mmol) and potassium acetate (294 mg, 3 mmol) in 1,4-dioxane (2.5 mL) washeated to 110° C. and maintained at that temperature overnight. Thereaction mixture was concentrated, and the product was used directly inthe next synthetic step without further isolation or purification.Assumed 100% yield.

LCMS (System 4, Method F): m/z 245 (M+H)⁺ (ESI +ve), at 0.14 min, 254nm.

A mixture of potassium carbonate (138 mg, 1.0 mmol),tetrakis(triphenylphosphine)palladium (0) (CAS: 95464-05-4) (58 mg, 0.05mmol),1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(183 mg, 0.75 mmol, assumed yield from previous step) and tert-butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (164 mg, 0.50 mmol) in 1,4-dioxane (2.2 mL) and water(0.26 mL) was heated to 110° C. and maintained at that temperatureovernight. The reaction mixture was then partitioned between EtOAc (5mL) and water (5 mL) and the phases were separated. The aqueous phasewas further extracted with EtOAc (3×5 mL) and all the organic phaseswere combined and concentrated to give the crude product, which waspurified by purification Method C to give tert-butyl(R)-(1-(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(83 mg, 41%) as a solid.

LCMS (System 4, Method F): m/z 410 (M+H)⁺ (ESI +ve), at 2.06 min, 254nm.

tert-Butyl(R)-(1-(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(83 mg, 0.20 mmol) was dissolved in DCM (2 mL), HCl solution in1,4-dioxane (4 M, 0.25 mL, 1.01 mmol) was added and the resultingmixture was stirred at RT overnight. After this time the whiteprecipitate was isolated to give4-[1-(difluoromethyl)pyrazol-3-yl]-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-aminedihydrochloride, Example 2-2 (69 mg, 98%).

The data for Example 2-2 are in Table 3.

Route E Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 3-1,(R)-4-(3-methyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

tert-Butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (1.0 g, 3.0 mmol),3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 9) (1.06 g, 3.63 mmol) and K₃PO₄ (1.90 g, 9.0 mol) weredissolved in 1,4-dioxane (16 mL) and water (4 mL) under nitrogen anddegassed for 20 min. Then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane complex (CAS: 95464-05-4) (245 mg, 0.3 mol) was addedunder a nitrogen atmosphere and the resulting mixture was stirred at 90°C. for 16 h. The reaction mixture was partitioned between H₂O (50 mL)and EtOAc (30 mL) and the aqueous layer was further extracted with EtOAc(3×50 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo to give the crude product, which waspurified by column chromatography (Normal-Phase neutral alumina, 9% MeOHin DCM) to give tert-butyl((3R)-1-(2-amino-6-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(1.2 g, 86%) as a solid.

LCMS (System 2, Method E): m/z 458 (M+H)⁺ (ESI +ve), at 3.96 min, 313nm.

tert-Butyl((3R)-1-(2-amino-6-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(1.2 g, 0.26 mmol) was dissolved in DCM (20 mL) and cooled to 0 C. HClsolution in 1,4-dioxane (4 M, 25 mL) was added dropwise and theresulting reaction mixture was stirred at 25° C. for 2 h. The solventswere removed in-vacuo and the residue was co-evaporated from toluene(2×30 mL) to give the crude product, which was purified by purificationMethod D to give(R)-4-(3-methyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 3-1 (520 mg, 73%) as a solid.

The data for Example 3-1 are in Table 3.

Route F Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 3-3,(R)-4-(3-(difluoromethyl)-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

To a nitrogen purged microwave vial was added5-bromo-3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(Intermediate 12) (100 mg, 0.31 mmol) dissolved in THF (0.40 mL) and thesolution was cooled to −78° C. under an atmosphere of nitrogen.n-Butyllithium solution in hexanes (2.5 M, 0.13 mL, 0.34 mmol) was thenadded dropwise to the solution before the dropwise addition oftriisopropyl borate (Intermediate 13) (0.08 mL, 0.34 mmol). The reactionmixture was then stirred at −78° C. for 1 h. Aqueous K₃PO₄ (0.5 M, 0.79mL, 0.40 mmol) was then added to the reaction mixture followed bytert-butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (70 mg, 0.21 mmol) and XPhos Pd G2 precatalyst (CAS:1310584-14-5) (7 mg, 0.009 mmol). The microwave vial was then sealed andheated to 40° C. (conventional heating) with stirring for 18 h. Thereaction mixture was added to a solution of water (20 mL) and saturatedaqueous NH₄Cl (0.4 mL) and extracted using ethyl acetate. The aqueouslayer was then re-extracted using ethyl acetate (×2). The combinedorganic extracts were filtered through a phase separator andconcentrated under reduced pressure, and the residue purified usingcolumn chromatography (basic silica, 0-50% ethyl acetate in petroleumether) to give the crude product (37 mg) as a solid. The solid wasfurther purified by purification Method E to give tert-butyl(R)-(1-(2-amino-6-(3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(9 mg, 5%).

LCMS (System 4, Method F): m/z 540 (M+H)⁺ (ESI +ve), at 2.70 min, 254nm.

To a solution of tert-butyl(R)-(1-(2-amino-6-(3-(difluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(8 mg, 0.01 mmol) dissolved in 1,4-dioxane (0.55 mL) was added HClsolution in 1,4-dioxane (4 M, 0.05 mL, 0.22 mmol). The reaction mixturewas stirred at room temperature for 6 h, then concentrated under reducedpressure and the residue co-evaporated from toluene. The crude productwas then purified using reversed phase column chromatography (C18silica, 0-10% MeCN in 0.2% NH₃ in water) to give(R)-4-(3-(difluoromethyl)-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 3-3 (2 mg, 47%).

The data for Example 3-3 are in Table 3.

Route G Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 3-4,(R)-4-(3-(difluoromethyl)-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amineditrifluoroacetate

3-(Trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Intermediate 15)(1.30 g, 7.20 mmol) was dissolved in acetonitrile (20 mL), CDI (1.40 g,8.66 mmol) was added portion-wise and the resulting mixture was stirredat room temperature for 2 h. Potassium 3-ethoxy-3-oxopropanoate(Intermediate 16) (1.22 g, 7.20 mmol) and MgCl₂ (823 mg, 7.20 mmol) werethen added and the resulting reaction mixture was stirred at roomtemperature for 14 h. The mixture was concentrated in-vacuo, the residuewas partitioned between H₂O (40 mL) and EtOAc (30 mL) and the layerswere separated. The aqueous layer was further extracted with EtOAc (2×30mL), the combined organic layers were dried (Na₂SO₄) and the solvent wasremoved in-vacuo. The crude product was purified by triturating withpentane (decanting off the solvent) and dried under high vacuum to giveethyl 3-oxo-3-(3-(trifluoromethyl)-1H-pyrazol-5-yl)propanoate (1.20 g,67%) as a gum.

LCMS (System 2, Method E): m/z 249 (M−H)⁻ (ESI −ve), at 4.47 min, 241nm.

Ethyl 3-oxo-3-(3-(trifluoromethyl)-1H-pyrazol-5-yl)propanoate (1.20 g,4.80 mmol) and guanidine hydrochloride (Intermediate 17) (1.37 g, 14.4mmol) were dissolved in methanol (20 mL) under nitrogen at 0° C. andstirred for 10 min. Potassium tert-butoxide (806 mg, 7.20 mmol) wasadded slowly under a nitrogen atmosphere and the resulting reactionmixture was stirred at 60° C. for 16 h. The organic solvent was removedin-vacuo to give the crude product, which was purified by trituratingwith pentane (decanting off the solvent) and dried under high vacuum togive 2-amino-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-4-ol (2.0g, crude) as a gum.

LCMS (System 2, Method E): m/z 246 (M+H)⁺ (ESI +ve), at 3.47 min, 237nm.

A mixture of2-amino-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-4-ol (2.0 g,8.16 mmol) and POCl₃ (5 mL) was stirred at 0° C. for 18 h. The reactionmixture was poured onto a mixture of ice and aqueous NaHCO₃, thenpartitioned between H₂O (50 mL) and EtOAc (40 mL) and the phases wereseparated. The aqueous phase was further extracted with EtOAc (2×40 mL)and the organic layers were all combined, dried (Na₂SO₄) and the solventwas removed in-vacuo. The residue was purified by column chromatography(Normal-Phase neutral activated alumina, 20% to 30% MeOH in DCM) to give4-chloro-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2-amine (350mg, 16%) as a gum.

LCMS (System 2, Method E): m/z 264/266 (M+H)⁺ (ESI +ve), at 4.57 min,239 nm.4-Chloro-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2-amine (200mg, 0.76 mmol) was dissolved in triethylamine (5 mL) and tert-butyl(R)-methyl(pyrrolidin-3-yl)carbamate (Intermediate 3) (228 mg, 1.14mmol) was added. The resulting reaction mixture was stirred at 90° C.for 6 h, then partitioned between H₂O (40 mL) and EtOAc (30 mL) and thephases were separated. The aqueous layer was further extracted withEtOAc (2×30 mL), the combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo. The residue was purified by columnchromatography (Normal-Phase neutral activated alumina, 5% to 10% MeOHin EtOAc) to give tert-butyl(R)-(1-(2-amino-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(315 mg, 97%) as a gum.

LCMS (System 2, Method E): m/z 428 (M+H)⁺ (ESI +ve), at 4.13 min, 243nm.

tert-Butyl(R)-(1-(2-amino-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(310 mg, 0.73 mmol) was dissolved 1,4-dioxane (3 mL) and the solutionwas cooled to 0° C. HCl solution in 1,4-dioxane (4 M, 8 mL) was addedand the resulting reaction mixture was stirred at room temperature for 7h. The reaction mixture was concentrated in-vacuo and the residue wastriturated with pentane (2×3 mL) to give the crude product as an HClsalt. The crude HCl salt was purified by purification Method F to give(R)-4-(3-(methylamino)pyrrolidin-1-yl)-6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2-amineditrifluoroacetate salt, Example 3-4 (60 mg, 19%) as a gum.

The data for Example 3-4 are in Table 3.

Route H Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 4-1,(R)-4-(4-methyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

4,6-Dichloropyrimidin-2-amine (Intermediate 1) (250 mg, 1.52 mmol),4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 19) (443 mg, 1.52 mmol) and K₂CO₃ (629 mg, 4.56 mmol) weredissolved in 1,4-dioxane (5 mL) and water (5 mL) under nitrogen anddegassed for 20 min. Then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane complex (CAS: 95464-05-4) (124 mg, 0.15 mmol) was addedunder a nitrogen atmosphere and the resulting mixture was stirred at 90°C. for 16 h. The reaction mixture was partitioned between H₂O (40 mL)and EtOAc (25 mL), and the aqueous layer was further extracted withEtOAc (3×25 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo to give the crude product, which waspurified by column chromatography (Normal-Phase activated Al₂O₃, 30%ethyl acetate in hexanes) to give4-chloro-6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine(255 mg, 57%) as a solid.

LCMS (System 2, Method E): m/z 294 (M+H)⁺ (ESI +ve), at 3.53 min, 234nm.

4-Chloro-6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine(255 mg, 0.87 mmol) and tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate(Intermediate 3) was dissolved in TEA (4 mL) under a nitrogen atmosphereand the resulting reaction mixture was heated to 130° C. in a CEMmicrowave and stirred at that temperature for 12 h. The reaction mixturewas then partitioned between H₂O (25 mL) and EtOAc (15 mL), and theaqueous layer was further extracted with EtOAc (2×15 mL). The combinedorganic layers were dried (Na₂SO₄) and the solvent was removed in-vacuoto give the crude product, which was purified by column chromatography(Normal-Phase, neutral activated alumina, 1 to 2% MeOH in DCM) to givetert-butyl((3R)-1-(2-amino-6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(101 mg, 25%) as a gum.

LCMS (System 2, Method E): m/z 458 (M+H)⁺ (ESI +ve), at 3.98 min, 278nm.

tert-Butyl((3R)-1-(2-amino-6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(100 mg, 0.22 mmol) was dissolved in DCM (5 mL), TFA (0.5 mL) was addedat 0° C. under an atmosphere of nitrogen and the resulting mixture wasstirred at room temperature for 18 h. The reaction mixture wasconcentrated and the residue was triturated with pentane (2×2 mL) togive the crude product, which was purified by purification Method G togive(R)-4-(4-methyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 4-1 (17 mg, 28%) as a solid.

The data for Example 4-1 are in Table 3.

Route I Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 4-2,(R)-4-(4-ethyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

To a nitrogen purged microwave vial was added4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate22) (500 mg, 2.21 mmol) dissolved in THF (2.9 mL) and the solution wascooled to −78° C. To this solution was then added n-butyllithiumsolution in hexanes (2.5 M, 0.97 mL, 2.43 mmol), dropwise over a periodof 10 minutes, followed by triisopropyl borate (Intermediate 13) (0.56mL, 2.43 mmol) added in a similar dropwise manner. The reaction mixturewas stirred at −78° C. for 1 h, then aqueous K₃PO₄ (0.5 M, 5.74 mL, 2.87mmol) was added, followed by tert-butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (217 mg, 0.66 mmol) and XPhos Pd G2 precatalyst (CAS:1310584-14-5) (52 mg, 0.04 mmol). The microwave vial was then sealed andheated to 40° C. (conventional heating) with stirring for 19 h. Thereaction mixture was added to a solution of water (49 mL) and saturatedaqueous NH₄Cl (1 mL) and extracted using ethyl acetate. The aqueouslayer was then re-extracted using ethyl acetate (2×50 mL). The combinedorganic extracts were then filtered through a phase separator,concentrated under reduced pressure and the residue was purified usingcolumn chromatography (silica, 0-100% ethyl acetate in petroleum ether)to give tert-butyl(R)-(1-(2-amino-6-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(87 mg, 25%).

LCMS (System 4, Method F): m/z 518 (M+H)⁺ (ESI +ve), at 2.58 min, 254nm.

To a solution of tert-butyl(R)-(1-(2-amino-6-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(87 mg, 0.17 mmol) dissolved in 1,4-dioxane (4 mL) was added HClsolution in 1,4-dioxane (4 M, 1.26 mL, 5.04 mmol). The reaction mixturewas stirred at room temperature for 45 min, then concentrated underreduced pressure and the residue co-evaporated from toluene. The residuewas purified by purification Method H to give(R)-4-(4-ethyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 4-2 (16 mg, 33%).

The data for Example 4-2 are in Table 3.

Route J Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 4-3,(R)-4-(4-chloro-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

To a nitrogen purged microwave vial was added4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate24) (646 mg, 2.78 mmol) dissolved in THF (3.7 mL). The solution wascooled to −78° C. and n-butyllithium solution in hexanes (2.5 M, 1.22mL, 3.05 mmol) was added dropwise over a period of 10 minutes before theaddition of triisopropyl borate (Intermediate 13) (0.7 mL, 3.05 mmol),added in a similar dropwise manner. The reaction mixture was stirred at−78° C. for 1 hour. Aqueous aqueous K₃PO₄ (0.5 M, 7.22 mL, 3.61 mmol)was then added to the reaction mixture followed by tert-butyl(R)-(1-(6-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl) pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate (Intermediate 26) (338 mg, 0.83 mmol)and XPhos Pd G2 precatalyst (CAS: 1310584-14-5) (66 mg, 0.08 mmol). Themicrowave vial was then sealed and heated to 40° C. conventionally withstirring for 1.5 h. The reaction mixture was added to a solution ofwater (49 mL) and saturated aqueous NH₄Cl (1 mL) and extracted usingethyl acetate (50 mL). The aqueous layer was further extracted withethyl acetate (2×50 mL) and the combined organic phases were filteredthrough a phase separator and concentrated under reduced pressure. Theresidue was then purified using column chromatography (silica, 0-25%ethyl acetate in petroleum ether) to give tert-butyl(R)-(1-(6-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(440 mg, 87%).

LCMS (System 4, Method F): m/z 602/604 (M+H)⁺ (ESI +ve), at 3.13 min,254 nm.

To a solution of give tert-butyl(R)-(1-(6-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(50 mg, 0.08 mmol) dissolved in MeCN (0.83 mL) was added aqueous HCl (4M, 1.25 mL, 5 mmol). The reaction mixture was stirred at roomtemperature for 2.5 h and at 40° C. for 2 h. An identical reaction onthe same scale was run in parallel, whereby the reaction mixture wasstirred at room temperature overnight. The two reaction mixtures werecombined and concentrated under reduced pressure. The residue wasco-evaporated from toluene to remove traces of water and then purifiedby purification Method I to give(R)-4-(4-chloro-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 4-3 (3.7 mg, 8%).

The data for Example 4-3 are in Table 3.

Route K Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 4-4,(R)-4-(4-methoxy-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

1, 4-Dioxane was degassed by passing a stream of nitrogen though theliquid for 15 min. A 5 mL microwave vial containing a stirrer bar wasflushed with a stream of nitrogen for 5 min, and then stoppered. To themicrowave vial was added (in this order): tert-butyl(R)-(1-(6-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 26) (107 mg, 0.26 mmol),4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate28) (102 mg, 0.45 mmol), tetrabutylammonium acetate (198 mg, 0.66 mmol)(very hygroscopic!), XPhos (CAS: 564483-18-7) (13 mg, 0.03 mmol) andXPhos Pd G2 precatalyst (CAS: 1310584-14-5) (9 mg, 0.01 mmol). The vialwas briefly flushed again with a stream of nitrogen and the degassed1,4-dioxane (3 mL) was added. The vial was sealed and heated withstirring at 100° C. on a hotplate for 66 h. The reaction was repeated ona similar scale and the two reaction solutions were combined using ethylacetate and concentrated onto flash silica (10 mL) in-vacuo. Theresulting powder was purified by flash chromatography (SiO₂, 20%-60%EtOAc in isohexane) to give tert-butyl(R)-(1-(2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(197 mg, 63%) as an oil.

LCMS (System 5, Method H): m/z 598 (M+H)⁺ (ESI +ve), at 2.21 min, 205nm.

A mixture of trifluoroacetic acid (2.7 mL) and water (0.3 mL) wasprepared and added to tert-butyl(R)-(1-(2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(197 mg, 0.33 mmol) to give a solution, which was stirred at RT under anatmosphere of nitrogen for 24 h. The dark red/black solution was dilutedwith an equal volume of toluene and concentrated in-vacuo. The residuewas co-evaporated from toluene to give a dark oil which slowlysolidified on standing to give a red/black solid. The solid was purifiedby purification Method J to give(R)-4-(4-methoxy-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amineExample 4-4 (17 mg, 17%) as a solid.

The data for Example 4-4 are in Table 3.

Route L Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 7-1,(R)-4-(3,4-dimethyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-aminedihydrochloride

3,4-Dimethyl-1H-pyrazole (496 mg, 5.0 mmol) was dissolved in THF (20mL), sodium hydride suspension in mineral oil (60%, 400 mg, 10 mmol) wasadded and the reaction was stirred at 0° C. for 1 h.(2-(Chloromethoxy)ethyl)trimethylsilane (Intermediate 21) (1.15 mL, 6.5mmol) was added and the reaction mixture was stirred at RT overnight.The reaction mixture was partitioned between water (25 mL) and EtOAc (40mL) and the aqueous phase was extracted further with EtOAc (3×50 mL).The combined organic phases were concentrated and the residue waspurified by flash column chromatography (normal phase SiO₂, 0% to 100%EtOAc in isohexane) to give a ˜1:1 mixture of3,4-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(Intermediate 44) (1100 mg, 97%) as an oil.

The data for Intermediate 44 are in Table 2.

A solution of a ˜1:1 mixture of3,4-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole and4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(Intermediate 44) (453 mg, 2.0 mmol) dissolved in THF (10 mL) was cooledto −78° C. To this solution was added n-butyllithium solution in hexanes(2.5 M, 2.0 mL, 5.0 mmol) and the reaction mixture was stirred at −78°C. for 1 h. To the reaction mixture was then added triisopropyl borate(Intermediate 13) (1.21 mL, 6.0 mmol) as a solution in THF (1 mL) at−78° C., and the resulting mixture was stirred for 1 h then allowed towarm to RT overnight. 2,3-Dimethylbutane-2,3-diol (Intermediate 38) (355mg, 3.0 mmol) was added followed by acetic acid (0.34 mL, 6.0 mmol)added 10 minutes later and the resulting mixture was stirred for anadditional 10 min. The reaction mixture was filtered through Celite andthe filtrate was concentrated to give a regio-isomeric mixture of3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleand4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleas an oil, which was used directly in the next reaction.

LCMS (System 4, Method F): m/z 252 (boronic acid—18)⁺ (ES⁺), at 2.72min, 254 nm.

A mixture of potassium carbonate (276 mg, 2.0 mmol),tetrakis(triphenylphosphine)palladium (0) (CAS: 95464-05-4) (116 mg,0.10 mmol), a regio-isomeric mixture of3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleand4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(352 mg, 1.0 mmol) and tert-butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (328 mg, 1.0 mmol) in 1,4-dioxane (2.2 mL) and water(0.10 mL) was heated to 110° C. and maintained at that temperatureovernight. The reaction mixture was then partitioned between DCM (5 mL)and water (5 mL), and the aqueous phase was further extracted with DCM(3×5 mL). The combined organic phases were concentrated and the residuewas purified by purification Method K to give either tert-butyl(R)-(1-(2-amino-6-(4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamateor tert-butyl(R)-(1-(2-amino-6-(3,4-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamateor a mixture of both isomers (6 mg, 1%).

LCMS (System 4, Method F): m/z 518 (M+H)⁺ (ES⁺), at 2.55 min, 254 nm.

tert-Butyl(R)-(1-(2-amino-6-(4,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamateor tert-butyl(R)-(1-(2-amino-6-(3,4-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamateor a mixture of both isomers (6 mg, 0.01 mmol) was dissolved in DCM (2mL) and HCl solution in 1,4-dioxane (4 M, 0.01 mL, 0.0400 mmol) wasadded. The mixture was stirred at RT overnight and the resultingprecipitate was removed by filtration to give(R)-4-(3,4-dimethyl-1H-pyrazol-5-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-aminedihydrochloride, Example 7-1 (3 mg, 72%).

The data for Example 7-1 are in Table 3.

Route M Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 11-1,((R)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

tert-Butyl(R)-(1-(2-amino-6-chloropyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(Intermediate 4) (1.0 g, 3.00 mmol),1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 80) (0.87 g, 3.90 mmol), K₂CO₃ (1.65 g, 12.0 mmol) andwater (4.0 mL) were dissolved in 1,4-dioxane (16.0 mL) under nitrogenand degassed for 20 min. Tricyclohexylphosphine (0.12 g, 0.4 mmol) andtris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3) (274 mg, 0.32mmol) were added under a nitrogen atmosphere and the mixture was stirredat 90° C. for 12 h. The reaction mixture was partitioned between H₂O (40mL) and EtOAc (25 mL), and the aqueous layer was further extracted withEtOAc (3×25 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo. The residue was purified by columnchromatography (Normal-Phase activated Al₂O₃, 0% to 10% MeOH in DCM) togive tert-butyl(R)-(1-(2-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(1.0 g, 86%) as a solid.

LCMS (System 3, Method D): m/z 388 (M+H)⁺ (ESI +ve), at 3.53 min, 202nm.

tert-Butyl(R)-(1-(2-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(1.0 g, 2.58 mmol) was dissolved in DCM (20 mL), TFA (5 mL) was added at0° C. and the mixture was stirred for 1 h at room temperature. Themixture was concentrated and the residue was triturated with pentane(2×10 mL). The residue was purified by purification Method L to afford((R)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 11-1 (500 mg, 68%) as a solid.

The data for Example 11-1 are in Table 3.

Route N Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 11-7,4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-methyl-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine

4,6-Dichloropyrimidin-2-amine (Intermediate 1) (500 mg, 3.06 mmol),1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Intermediate 80) (0.68 g, 3.07 mmol) and NaHCO₃ (0.967 g, 9.20 mmol)were dissolved in a mixture of 1,4-dioxane (10 mL) and water (2 mL)under nitrogen and the resulting mixture was degassed for 20 min.Tetrakis(triphenylphosphine)palladium (0) (CAS: 95464-05-4) (0.355 g,0.306 mmol) was added under a nitrogen atmosphere and the resultingmixture was stirred at 50-70° C. for 12 h. The reaction mixture was thenpartitioned between H₂O (40 mL) and EtOAc (40 mL), and the aqueous layerwas further extracted with EtOAc (3×20 mL). The combined organic layerswere dried (Na₂SO₄) and the solvent was removed in-vacuo. The residuewas purified by column chromatography (Normal-Phase activated Al₂O₃, 20%ethyl acetate in hexane) to give4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (Intermediate89) (250 mg, 22%) as a solid.

The data for Intermediate 89 are in Table 2.

Benzyl methyl(3-methylpyrrolidin-3-yl)carbamate hydrochloride(Intermediate 88) (222 mg, 0.78 mmol) and4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (Intermediate89) were dissolved in N-methyl-2-pyrrolidinone (8 mL) under anatmosphere of nitrogen and potassium fluoride (156 mg, 2.68 mmol) wasadded. The resulting reaction mixture was stirred at 160° C. for 4 husing a CEM microwave. The mixture was then partitioned between H₂O (35mL) and EtOAc (25 mL), and the aqueous layer was further extracted withEtOAc (2×25 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in-vacuo. The residue was purified by columnchromatography (Normal-Phase neutral activated Al₂O₃, 2% to 6% MeOH inEtOAc) to give benzyl(1-(2-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-methylpyrrolidin-3-yl)(methyl)carbamate(190 mg, 49%) as a solid.

LCMS (System 3, Method E): m/z 436 (M+H)⁺ (ESI +ve), at 3.83 min, 247nm.

Benzyl(1-(2-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-3-methylpyrrolidin-3-yl)(methyl)carbamate(190 mg, 0.44 mmol) was dissolved in MeOH (15 mL) and 10% palladiumhydroxide on carbon (50% moisture, 100 mg) was added. The vessel wasthen purged with hydrogen and stirred under an atmosphere of hydrogen at25° C. for 6 h. The reaction mixture was filtered through Celite,washing the catalyst with MeOH, and the filtrate was concentratedin-vacuo to give the crude product, which was triturated with pentane(2×2 mL) to remove non-polar impurities. The product was purified bypurification Method M followed by purification Method N to give4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-methyl-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 11-7 Isomer 1 (19 mg, 15%) as a solid and4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-methyl-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine,Example 11-7 Isomer 2 (20 mg, 15%) as a solid.

The data for Example 11-7 Isomer 2 are in Table 3.

Route O Typical Procedure for the Preparation of Pyrimidines asExemplified by the Preparation of Example 11-8,4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-2-amine

4-Chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (Intermediate89) (150 mg, 0.672 mmol) was dissolved in MeCN:TEA (1:1, 10 mL) andtert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate(Intermediate 90) (228 mg, 1.01 mmol) was added at RT. The mixture wasstirred at 120° C. for 6 h using a CEM microwave. The reaction mixturewas concentrated in-vacuo, and the residue was purified by columnchromatography (Neutral Al₂O₃, 0% to 10% MeOH:DCM) to give tert-butyl6-(2-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylateas a solid (150 mg, 54%).

LCMS (System 3, Method D): m/z 414 (M+H)⁺ (ESI +ve), at 3.75 min, 254nm.

tert-Butyl6-(2-amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate(150 mg, 3.63 mmol) was dissolved DCM (10 mL) and TFA (2 mL) was addedat 0° C. The resulting mixture was stirred for 1 h at room temperature,then concentrated in-vacuo and the residue was triturated with pentane(2×10 mL) to give crude product. The crude product was purified bypurification Method O followed by purification Method P to give4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-2-amine,Example 11-8 Isomer 1 (20 mg, 18%) and4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-2-amine,Example 11-8 Isomer 2 (10 mg, 9%).

The data for Example 11-7 Isomer 1 and Isomer 2 are in Table 3.

Route P Typical Procedure for the Preparation of Pyridines asExemplified by the Preparation of Example 14-1,(R)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(3-(methylamino)pyrrolidin-1-yl)pyridin-2-aminedihydrochloride

To a nitrogen purged microwave vial containing XPhos (CAS: 564483-18-7)(93 mg, 0.19 mmol),4-chloro-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate99) (210 mg, 0.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (CAS:51364-51-3) (86 mg, 0.09 mmol) and (R)-methyl(pyrrolidin-3-yl)carbamate(Intermediate 3) (208 mg, 1.04 mmol) was added toluene (5 mL). Thereaction vessel was purged with nitrogen and sodium tert-butoxide (272mg, 2.83 mmol) was added. The vessel was then sealed and heatedconventionally at 110° C. for 16 h. The reaction mixture was partitionedbetween EtOAc (5 mL) and water (5 mL) and the aqueous phase was furtherextracted with EtOAc (3×5 mL). The combined organic phases wereconcentrated and the residue was purified by flash column chromatography(normal phase SiO₂, 0% to 10% MeOH in DCM) to give the crude productwhich was further purified by purification Method Q to give tert-butyl(R)-(1-(2-amino-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)pyrrolidin-3-yl)(methyl)carbamate(5 mg, 1%) as an oil.

LCMS (System 4, Method F): m/z 387 (M+H)⁺ (ES⁺), at 2.07 min, 254 nm.

tert-Butyl (R)-(1-(2-amino-6-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl) pyrrolidin-3-yl)(methyl)carbamate (5 mg, 0.010 mmol) wasdissolved in DCM (2 mL), HCl solution in 1,4-dioxane (4 M, 0.01 mL, 0.06mmol) was added and the resulting mixture was stirred at RT overnight.After this time the white precipitate was filtered off to give(R)-6-(1,5-dimethyl-1H-pyrazol-4-yl)-4-(3-(methylamino)pyrrolidin-1-yl)pyridin-2-aminedihydrochloride, Example 14-1 (3 mg, 78%).

TABLE 2 Intermediates Table 2 Intermediate Synthetic IntermediatesNumber Name Route Used Data 1 4,6-Dichloropyrimidin-2-amine — —Commercially available, CAS: 56-05-3 2 5-(4,4,5,5-Tetramethyl-1,3,2- — —Commercially available, dioxaborolan-2-yl)-1H-pyrazole CAS: 844501-71-93 tert-Butyl (R)-methyl(pyrrolidin- — — Commercially available,3-yl)carbamate CAS: 392338-15-7 4 tert-Butyl (R)-(1-(2-amino-6- B 1 and3 LCMS (System 2, Method E): m/z chloropyrimidin-4-yl)pyrrolidin-3-(Step 1) 328 (M + H)⁺ (ES⁺), yl)(methyl)carbamate at 3.77 min, 240 nm 51-Methyl-5-(4,4,5,5-tetramethyl- — — Commercially available,1,3,2-dioxaborolan-2-yl)-1H- CAS: 847818-74-0 pyrazole 61-Methyl-3-(4,4,5,5-tetramethyl- — — Commercially available,1,3,2-dioxaborolan-2-yl)-1H- CAS: 1020174-04-2 pyrazole 73-Bromo-1-(difluoromethyl)-1H- — — Commercially available, pyrazole CAS:1224194-42-6 8 Bis(pinacolato)diboron — — Commercially available, CAS:73183-34-3 9 3-Methyl-1-(tetrahydro-2H- — — Commercially available,pyran-2-yl)-5-(4,4,5,5- CAS: 1486485-62-4tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole 103-Cyclopropyl-1-(tetrahydro-2H- — — Commercially available,pyran-2-yl)-5-(4,4,5,5- CAS: 1486485-57-7tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole 11 5-Bromo-1-((2- — —Commercially available, (trimethylsilyl)ethoxy)methyl)- Alichem (China)Co. Ltd. 1H-pyrazole-3-carbaldehyde Product code: 049000432 125-Bromo-3-(difluoromethyl)-1- 1 11 ¹H NMR (400 MHz, Chloroform-d) δ((2-(trimethylsilyl)ethoxy)methyl)- 6.62 (t, J = 54.9 Hz, 1H), 6.59 (s,1H-pyrazole 1H), 5.49 (s, 1H), 3.65-3.56 (m, 2H), 0.95-0.86 (m, 2H),0.01-−0.05 (m, 9H). 13 Triisopropyl borate — — Commercially available,CAS: 5419-55-6 14 Ethyl 3-(trifluoromethyl)-1H- — — Commerciallyavailable, pyrazole-5-carboxylate CAS: 129768-30-5 153-(Trifluoromethyl)-1H-pyrazole- 2 14 LCMS (System 2, Method E): m/z5-carboxylic acid 179 (M − H)⁻ (ES⁻), at 2.47 min, 230 nm 16 Potassium3-ethoxy-3- — — Commercially available, oxopropanoate CAS: 6148-64-7 17Guanidine hydrochloride — — Commercially available, CAS: 50-01-1 18tert-Butyl (R)-pyrrolidin-3- — — Commercially available, ylcarbamateCAS: 122536-77-0 19 4-Methyl-1-(tetrahydro-2H- — — Commerciallyavailable, pyran-2-yl)-5-(4,4,5,5- CAS: 1492954-33-2tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole 20 4-Ethyl-1H-pyrazole— — Commercially available, CAS: 17072-38-7 21 (2- — — Commerciallyavailable, (Chloromethoxy)ethyl)trimethylsilane CAS: 76513-69-4 224-Ethyl-1-((2- 3 20 and 21 ¹H NMR (400 MHz, Chloroform-d) δ(trimethylsilyl)ethoxy)methyl)- 7.36 (s, 1H), 7.33-7.31 (m, 1H),1H-pyrazole 5.34 (s, 2H), 3.57-3.48 (m, 2H), 2.54-2.44 (m, 2H),1.22-1.14 (m, 3H), 0.92-0.83 (m, 2H), −0.01-−0.09 (m, 9H). 234-Chloro-1H-pyrazole — — Commercially available, CAS: 15878-00-9 244-Chloro-1-((2- 3 23 and 21 ¹H NMR (400 MHz, Chloroform-d) δ(trimethylsilyl)ethoxy)methyl)- 7.58-7.50 (m, 1H), 7.47-7.41 (m,1H-pyrazole 1H), 5.36 (s, 2H), 3.59-3.47 (m, 2H), 0.95-0.83 (m, 2H),−0.03 (s, 9H). 25 Hexane-2,5-dione — — Commercially available, CAS:110-13-4 26 tert-Butyl (R)-(1-(6-chloro-2-(2,5- 4 1, 25 and 3 LCMS(System 4, Method F): m/z dimethyl-1H-pyrrol-1- 406/408 (M + H)⁺ (ES⁺),yl)pyrimidin-4-yl)pyrrolidin-3- at 2.72 min, 254 nm yl)(methyl)carbamate27 4-Methoxy-1H-pyrazole — — Commercially available, CAS: 14884-01-6 284-Methoxy-1-((2- 3 27 and 21 LCMS (System 5, Method H): m/z(trimethylsilyl)ethoxy)methyl)- 229 (M + H)⁺ (ES⁺), 1H-pyrazole at 1.47min, 205 nm 29 4-Methyl-1H-pyrazole-5- — — Commercially available,carboxylic acid CAS: 82231-51-4 30 Ethyl 5-methyl-1H-pyrazole-3- — —Commercially available, carboxylate CAS: 4027-57-0 311,5-Dimethyl-1H-pyrazole-3- 5 29 LCMS (System 1, Method B): m/zcarboxylic acid 141 (M + H)⁺ (ESI +ve), at 1.23 min, 235 nm 321-(Difluoromethyl)-5-methyl-1H- — — Commercially available,pyrazole-3-carboxylic acid CAS: 1004643-64-4 33 Ethyl4-methyl-1H-pyrazole-3- — — Commercially available, carboxylate CAS:6076-12-6 34 1,4-Dimethyl-1H-pyrazole-3- 5 33 LCMS (System 2, Method E):m/z carboxylic acid 141 (M + H)⁺ (ESI +ve), at 1.49 min, 237 nm 35Sodium 2-chloro-2,2- — — Commercially available, difluoroacetate CAS:1895-39-2 36 1-(Difluoromethyl)-4-methyl-1H- 6 33 and 35 LCMS (System 3,Method D): m/z pyrazole-3-carboxylic acid 177 (M + H)⁺ (ESI +ve), at1.12 min, 202 nm 37 3,4-Dimethyl-1H-pyrazole — — Commercially available,CAS: 2820-37-3 38 2,3-Dimethylbutane-2,3-diol — — Commerciallyavailable, CAS: 76-09-5 39 4-Chloro-3-methyl-1H-pyrazole — —Commercially available, CAS: 15878-08-7 40 3-Ethyl-4-methyl-1H-pyrazole— — Commercially available, CAS: 7231-33-6 41 3-Iodo-1,4,5,6- — —Commercially available, tetrahydrocyclopenta[c]pyrazole CAS:1426424-00-1 42 Trimethyl borate — — Commercially available, CAS:121-43-7 43 3-(4,4,5,5-Tetramethyl-1,3- — — Commercially available,dioxolan-2-yl)-1H-indazole CAS: 937366-55-7 44 Mixture of3,4-dimethyl-1-((2- L 37 and 21 ¹H NMR (400 MHz, Chloroform-d) δ(trimethylsilyl)ethoxy)methyl)- (Step 1) 7.26, 7.24 (2 × s, 1H), 5.37,5.29 (2 × 1H-pyrazole and 4,5-dimethyl-1- s, 2H), 3.56-3.50 (m, 2H),2.24, ((2-(trimethylsilyl)ethoxy)methyl)- 2.20 (2 × s, 3H), 2.01-1.98(m, 1H-pyrazole 3H), 0.93-0.84 (m, 2H), −0.02, −0.03 (2 × s, 9H). 45tert-Butyl (R)-(1-(2-amino-6- B 1 and 18 LCMS (System 4, Method F): m/zchloropyrimidin-4-yl)pyrrolidin-3- (Step 1) 314/316 (M + H)+ (ES+), at1.86 min, yl)carbamate 254 nm 46 Mixture of 4-chloro-3-methyl-1- 3 39and 21 LCMS (System 4, Method F): m/z((2-(trimethylsilyl)ethoxy)methyl)- 189/191 (M-SiMe2 + H)⁺ (ES⁺),1H-pyrazole and 4-chloro-5- at 3.08 min, 254 nm methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole 474-(4,4,5,5-Tetramethyl-1,3,2- — — Commercially available,dioxaborolan-2-yl)-1H-pyrazole CAS: 269410-08-4 481-Methyl-4-(4,4,5,5-tetramethyl- — — Commercially available,1,3,2-dioxaborolan-2-yl)-1H- CAS: 761446-44-0 pyrazole 491-Ethyl-4-(4,4,5,5-tetramethyl- — — Commercially available,1,3,2-dioxaborolan-2-yl)-1H- CAS: 847818-70-6 pyrazole 501-Cyclopropyl-4-(4,4,5,5- — — Commercially available,tetramethyl-1,3,2-dioxaborolan- CAS: 1151802-22-0 2-yl)-1H-pyrazole 511-Cyclobutyl-4-(4,4,5,5- — — Commercially available,tetramethyl-1,3,2-dioxaborolan- CAS: 1002309-48-9 2-yl)-1H-pyrazole 521-(Difluoromethyl)-4-(4,4,5,5- — — Commercially available,tetramethyl-1,3,2-dioxaborolan- CAS: 1206640-82-5 2-yl)-1H-pyrazole 534-(4,4,5,5-Tetramethyl-1,3,2- — — Commercially available,dioxaborolan-2-yl)-1- CAS: 1046831-98-4 (trifluoromethyl)-1H-pyrazole 544-(4,4,5,5-Tetramethyl-1,3,2- — — Commercially available,dioxaborolan-2-yl)-1-(2,2,2- CAS: 1049730-42-8trifluoroethyl)-1H-pyrazole 55 2-(4-(4,4,5,5-Tetramethyl-1,3,2- — —Commercially available, dioxaborolan-2-yl)-1H-pyrazol-1- CAS:1040377-08-9 yl)ethan-1-ol 56 1-(2-Methoxyethyl)-4-(4,4,5,5- — —Commercially available, tetramethyl-1,3,2-dioxaborolan- CAS: 847818-71-72-yl)-1H-pyrazole 57 1-(Oxetan-3-yl)-4-(4,4,5,5- — — Commerciallyavailable, tetramethyl-1,3,2-dioxaborolan- CAS: 1339890-99-12-yl)-1H-pyrazole 58 3-(4-(4,4,5,5-Tetramethyl-1,3,2- — — Commerciallyavailable, dioxaborolan-2-yl)-1H-pyrazol-1- CAS: 1022092-33-6yl)propanenitrile 59 2-(4-(4,4,5,5-Tetramethyl-1,3,2- — — Commerciallyavailable, dioxaborolan-2-yl)-1H-pyrazol-1- CAS: 1093307-35-7yl)acetonitrile 60 tert-Butyl 3-oxopiperidine-1- — — Commerciallyavailable, carboxylate CAS: 98977-36-7 61 4-Bromo-1H-pyrazole — —Commercially available, CAS: 2075-45-8 62 Ethyl chloroformate — —Commercially available, CAS: 541-41-3 63 Ethyl3-(4-(4,4,5,5-tetramethyl- 7 60, 61, 62 and 8 LCMS (System 2, Method E):m/z 1,3,2-dioxaborolan-2-yl)-1H- 350 (M + H)⁺ (ESI +ve), at 4.14 min,pyrazol-1-yl)piperidine-1- 202 nm carboxylate 64 tert-Butyl azetidin-3-— — Commercially available, yl(methyl)carbamate CAS: 943060-59-1hydrochloride 65 tert-Butyl (1-(2-amino-6- B 1 and 64 LCMS (System 4,Method F): m/z chloropyrimidin-4-yl)azetidin-3- (Step 1) 258/260 (M-56 +H)+ (ES+), yl)(methyl)carbamate (DIPEA at 1.97 min, 254 nm used insteadof TEA) 68 3-Methyl-4-(4,4,5,5-tetramethyl- — — Commercially available,1,3,2-dioxaborolan-2-yl)-1H- CAS: 936250-20-3 pyrazole 694-Bromo-3-ethyl-1H-pyrazole — — Commercially available, CAS: 15802-79-670 3,4-Dihydro-2H-pyran — — Commercially available, CAS: 110-87-2 714-Bromo-3-ethyl-1-(tetrahydro- 8 69 and 70 ¹H NMR (400 MHz,Chloroform-d) δ 2H-pyran-2-yl)-1H-pyrazole 1.22-1.29 (m, 3H), 1.50-1.75(m, 4H), 1.97-2.06 (m, 2H), 2.58- 2.79 (m, 2H), 3.99-4.16 (m, 2H),5.23-5.32 (m, 1H), 7.55 (s, 1H). 72 3-Ethyl-1-(tetrahydro-2H-pyran- D 71and 8 LCMS (System 2, Method E): m/z 2-yl)-4-(4,4,5,5-tetramethyl-(Step 1) 307 (M + H)⁺ (ESI +ve), at 4.47 min,1,3,2-dioxaborolan-2-yl)-1H- 202 nm pyrazole 73 3-lsopropyl-4-(4,4,5,5-— — Commercially available, tetramethyl-1,3,2-dioxaborolan- CAS:1983152-92-6 2-yl)-1H-pyrazole 74 3-Cyclopropyl-4-(4,4,5,5- — —Commercially available, tetramethyl-1,3,2-dioxaborolan- CAS: 957345-32-32-yl)-1H-pyrazole 75 4-Bromo-3-(difluoromethyl)-1H- — — Commerciallyavailable, pyrazole CAS: 1451392-65-6 76 4-Bromo-3-(difluoromethyl)-1- 875 and 70 LCMS (System 1, Method B): m/z (tetrahydro-2H-pyran-2-yl)-1H-281/283 (M + H)⁺ (ESI +ve), at 1.70 pyrazole min, 270 nm 773-(Difluoromethyl)-1-(tetrahydro- D 76 and 8 LCMS (System 1, Method B):m/z 2H-pyran-2-yl)-4-(4,4,5,5- (Step 1) 329 (M + H)⁺ (ESI +ve), at 1.88min, tetramethyl-1,3,2-dioxaborolan- 228 nm 2-yl)-1H-pyrazole 784-(4,4,5,5-Tetramethyl-1,3,2- — — Commercially available,dioxaborolan-2-yl)-3- CAS: 1218790-40-9 (trifluoromethyl)-1H-pyrazole 793,5-Dimethyl-1-(tetrahydro-2H- — — Commercially available,pyran-2-yl)-4-(4,4,5,5- CAS: 1126779-11-0tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole 801,3-Dimethyl-4-(4,4,5,5- — — Commercially available,tetramethyl-1,3,2-dioxaborolan- CAS: 1046832-21-6 2-yl)-1H-pyrazole 813-Ethyl-1-methyl-4-(4,4,5,5- — — Commercially available,tetramethyl-1,3,2-dioxaborolan- CAS: 1619991-78-4 2-yl)-1H-pyrazole 823-Cyclopropyl-1-methyl-4- — — Commercially available,(4,4,5,5-tetramethyl-1,3,2- CAS: 1257637-82-3dioxaborolan-2-yl)-1H-pyrazole 83 1-Methyl-4-(4,4,5,5-tetramethyl- — —Commercially available, 1,3,2-dioxaborolan-2-yl)-3- CAS: 1218790-53-4(trifluoromethyl)-1H-pyrazole 84 4-Bromo-1-methyl-1H-pyrazole- — —Commercially available, 3-carbonitrile CAS: 287922-71-8 854-Bromo-1-(difluoromethyl)-3- — — Commercially available,methyl-1H-pyrazole CAS: 1215295-92-3 86 tert-Butyl 3-amino-3- — —Commercially available, methylpyrrolidine-1-carboxylate CAS:1158758-59-8 87 Benzyl chloroformate — — Commercially available, CAS:501-53-1 88 Benzyl methyl(3- 9 86 and 87 LCMS (System 3, Method C): m/zmethylpyrrolidin-3-yl)carbamate 249 (M + H)⁺ (ESI +ve), at 7.99 min,hydrochloride 202 nm 89 4-Chloro-6-(1,3-dimethyl-1H- M LCMS (System 3,Method E): m/z pyrazol-4-yl)pyrimidin-2-amine (Step 1) 224/226 (M + H)⁺(ESI +ve), at 2.79 min, 254 nm 90 tert-Butyl octahydro-1H- — —Commercially available, pyrrolo[3,4-b]pyridine-1- CAS: 159877-36-8carboxylate 91 1,5-Dimethyl-4-(4,4,5,5- — — Commercially available,tetramethyl-1,3,2-dioxaborolan- CAS: 1036991-40-8 2-yl)-1H-pyrazole 924-Bromo-1-methyl-1H-pyrazole- — — Commercially available, 5-carbonitrileCAS: 327099-80-9 93 4-Bromo-1-(difluoromethyl)-5- — — Commerciallyavailable, methyl-1H-pyrazole CAS: 1243250-04-5 943-(4,4,5,5-Tetramethyl-1,3,2- — — Commercially available,dioxaborolan-2-yl)-5,6-dihydro- CAS: 1314138-13-04H-pyrrolo[1,2-b]pyrazole 95 1,3,5-Trimethyl-4-(4,4,5,5- — —Commercially available, tetramethyl-1,3,2-dioxaborolan- CAS: 844891-04-92-yl)-1H-pyrazole 98 4,6-Dichloropyridin-2-amine — — Commerciallyavailable, CAS: 116632-24-7 99 4-Chloro-6-(1,5-dimethyl-1H- Q 98 and 91LCMS (System 2, Method E): m/z pyrazol-4-yl)pyridin-2-amine 223/225 (M +H)+ (ESI +ve), at 3.00 min, 234 nm. 100 3-(4,4,5,5-Tetramethyl-1,3,2- —— Commercially available, dioxaborolan-2-yl)cyclopent-2- CAS:1370008-65-3 en-1-one 101 3-Ethyl-1H-pyrazole — — Commerciallyavailable, CAS: 13808-71-4 102 3-Ethyl-1-((2- 3 101 and 21 LCMS (System4, Method F): m/z (trimethylsilyl)ethoxy)methyl)- 169 (M-SiMe₂ + H)⁺(ES⁺), 1H-pyrazole at 2.39 min, 200-400 nm 103 tert-Butyl(S)-methyl(pyrrolidin-3- — — Commercially available, yl)carbamate CAS:169750-01-0 104 N,3-Dimethylpyrrolidin-3-amine — — Commerciallyavailable, CAS: 685879-85-0 105 tert-Butyl azetidin-3-ylcarbamate — —Commercially available, CAS: 91188-13-5 106 N,3-dimethylazetidin-3-amine— — Commercially available, dihydrochloride CAS: 2170250-39-0 107tert-Butyl hexahydropyrrolo[3,4- — — Commercially available,b]pyrrole-1(2H)-carboxylate CAS: 185693-02-1 108 tert-Butyl(4aR,7aR)-octahydro- — — Commercially available,1H-pyrrolo[3,4-b]pyridine-1- CAS: 186201-89-8 carboxylate 109 Ethyl4-formyl-1H-pyrazole-3- — — Commercially available, carboxylate CAS:179692-09-2 110 1-(Chloromethyl)-4- — — Commercially available,methoxybenzene CAS: 824-94-2 111 4-(Difluoromethyl)-1-(4- 10  109 and110 LCMS (System 1, Method B): no methoxybenzyl)-1H-pyrazole-3- massion, at 1.50 min, 235 nm. carboxylic acid 112 Ethyl4-(trifluoromethyl)-1H- — — Commercially available,pyrazole-3-carboxylate CAS: 934758-94-8 113 Ethyl1-(tetrahydro-2H-pyran-2- 8 112 and 70 LCMS (System 2, Method E): m/zyl)-4-(trifluoromethyl)-1H- 293 (M + H)⁺ (ES⁺), pyrazole-3-carboxylateat 4.21 min, 202 nm 114 1-(Tetrahydro-2H-pyran-2-yl)-4- 2 113  LCMS(System 2, Method E): m/z (trifluoromethyl)-1H-pyrazole-3- 265 (M + H)⁺(ES⁺), carboxylic acid at 1.82 min, 202 nm 115 4-Fluoro-1H-pyrazole — —Commercially available, CAS: 35277-02-2 116 4-Fluoro-1-((2- 3 115  ¹HNMR (400 MHz, Chloroform-d) (trimethylsilyl)ethoxy)methyl)- δ 0.02 (s,9H), 0.84-0.94 (m, 2H), 1H-pyrazole 3.48-3.56 (m, 2H), 5.29-5.34 (m,2H), 7.36-7.39 (m, 1H), 7.42- 7.45 (m, 1H). 117 tert-Butyl(R)-(1-(2-(2,5- K 116 and 26 LCMS (System 4, Method F): m/zdimethyl-1H-pyrrol-1-yl)-6-(4- (Step 1) 586 (M + H)⁺ (ES⁺),fluoro-1-((2- at 3.12 min, 254 nm (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrimidin-4- yl)pyrrolidin-3-yl)(methyl)carbamate 118tert-Butyl (R)-(1-(2-amino-6-(4- 11  117  LCMS (System 5, Method H): m/zfluoro-1-((2- 508 (M + H)⁺ (ES⁺), (trimethylsilyl)ethoxy)methyl)- at1.84 min, 205 nm 1H-pyrazol-5-yl)pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)carbamate 119 tert-Butyl azetidin-3- — —Commercially available, yl(methyl)carbamate CAS: 577777-20-9 1204-bromo-1H-Pyrazole-3- — — Commercially available, carboxylic acid, CAS:13745-17-0 121 4-(methylthio)-1H-pyrazole-3- 12  LCMS (System 1, MethodB): m/z carboxylic acid 159 (M + H)⁺ (ES⁺), at 1.22 min, 230 nm 1224,5-Dimethyl-1H-pyrazole-3- — — Commercially available, carboxylic acidCAS: 89831-40-3 123 3-Methyl-4-(trifluoromethyl)-1H- — — Commerciallyavailable, pyrazole CAS: 864239-61-2 124 1:1 mixture of 3-methyl-4- 3123  LCMS (System 4, Method F): no (trifluoromethyl)-1-((2- mass ion, at2.59 min, 254 nm (trimethylsilyl)ethoxy)methyl)- 1H-pyrazole and5-methyl-4- (trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole 125 4-fluoro-5-methyl-1H-pyrazole-3- — — Commerciallyavailable, carboxylic acid CAS: 681034-58-2 1264-Chloro-5-methyl-1H-pyrazole- — — Commercially available, 3-carboxylicacid CAS: 29400-84-8 127 4-methoxy-5-methyl-1- 13  30 LCMS (System LCMS2, Method (tetrahydro-2H-pyran-2-yl)-1H- E): m/z 241 (M + H)⁺ (ES⁺),pyrazole-3-carboxylic acid at 1.71 min, 232 nm 1283-(Difluoromethyl)-4-methyl-1H- — — Commercially available, pyrazoleCAS: 1245772-27-3 129 (3-(difluoromethyl)-4-methyl-1- 14  128  LCMS(System LCMS 2, Method (tetrahydro-2H-pyran-2-yl)-1H- E): m/z 261 (M +H)⁺ (ES⁺), pyrazol-5-yl) boronic acid at 3.06 min, 234 nm 1304-Methyl-3- — — Commercially available, trifluoromethylpyrazole CAS:153085-14-4 131 4-methyl-3-(trifluoromethyl)-1- 3 130  LCMS (System LCMS4, Method ((2-(trimethylsilyl)ethoxy)methyl)- F): no mass ion, at 2.68min, 254 nm 1H-pyrazole 132 5-Ethyl-4-fluoro-1H-pyrazole-3- — —Commercially available, carboxylicacid CAS: 681034-63-9 1333-Chloro-4-methyl-1H-pyrazole — — Commercially available, CAS:134589-56-3 134 3-chloro-4-methyl-1-((2- 3 133  LCMS (System LCMS 4,Method (trimethylsilyl)ethoxy)methyl)- F): no mass ion, at 2.57 min, 254nm 1H-pyrazole contains some regioisomer 135 4,5-Dichloro-1H-pyrazole-3-— — Commercially available, carboxylic acid CAS: 115964-19-7 1365-chloro-4-methyl-1H-pyrazole- — — Commercially available, 3-carboxylicacid CAS: 1934369-17-1

Table 3—Example Compounds

TABLE 3 Ex. Synthetic Method Isolation No. Name and Intermediates UsedMethod 1-1 (R)-4-(3-(Methylamino)pyrrolidin-1- A RP HPLCyl)-6-(1H-pyrazol-5-yl)pyrimidin-2-amine 1, 2 and 3 1-2(R)-4-(1-Methyl-1H-pyrazol-5-yl)-6-(3- B Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 1, 3 and 5 fromdeprotection dihydrochloride step 2-1 (R)-4-(1-Methyl-1H-pyrazol-3- C RPHPLC yl)-6-(3-(methylamino)pyrrolidin-1- 4 and 6 yl)pyrimidin-2-amine2-2 (R)-4-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-6-(3- D Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 7, 8 and 4 fromdeprotection dihydrochloride step 3-1 (R)-4-(3-Methyl-1H-pyrazol-5- E RPHPLC yl)-6-(3-(methylamino)pyrrolidin-1- 4 and 9 yl)pyrimidin-2-amine3-2 (R)-4-(3-Cyclopropyl-1H-pyrazol-5-yl)-6-(3- D Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine (Steps 2 and 3) fromdeprotection dihydrochloride 10 and 4 step 3-3(R)-4-(3-(Difluoromethyl)-1H-pyrazol-5-yl)-6-(3- F RP(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 12, 13 and 4chromatography 3-4 (R)-4-(3-(Methylamino)pyrrolidin-1-yl)-6-(3- G RPHPLC (trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2- 15, 16, 17 and 3amine ditrifluoroacetate 3-5 (R)-4-(3-Aminopyrrolidin-1-yl)-6-(3- G RPHPLC (trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2- 15, 16, 17 and 18amine 4-1 (R)-4-(4-Methyl-1H-pyrazol-5-yl)-6-(3- H RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 1, 19 and 3 4-2(R)-4-(4-Ethyl-1H-pyrazol-5-yl)-6-(3- I RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 22, 13 and 4 4-3(R)-4-(4-Chloro-1H-pyrazol-5-yl)-6-(3- J RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 24, 13 and 26 4-4(R)-4-(4-Methoxy-1H-pyrazol-5-yl)-6-(3- K RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 28 and 26 4-5(R)-4-(3-Aminopyrrolidin-1-yl)-6-(4- G Free basemethyl-1H-pyrazol-5-yl)pyrimidin-2-amine 29, 16, 17 and 18 generatedfrom TFA/DCM used in TFA salt final step 5-1(R)-4-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 31, 16, 17 and 3diformate TFA/DCM used in final step 5-2(R)-4-(1-(Difluoromethyl)-5-methyl-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 32, 16, 17 and 3 TFA/DCMused in final step 6-1 (R)-4-(1,4-Dimethyl-1H-pyrazol-3-yl)-6-(3- G RPHPLC (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 34, 16, 17 and 3TFA/DCM used in final step 6-2(R)-4-(1-(Difluoromethyl)-4-methyl-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 36, 16, 17 and 3 TFA/DCMused in final step 7-1 (R)-4-(3,4-Dimethyl-1H-pyrazol-5-yl)-6-(3- LSolid isolated (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 37, 21,13, 38 and 4 from deprotection dihydrochloride step 7-2(R)-4-(4-Chloro-3-methyl-1H-pyrazol-5-yl)-6-(3- L RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 39, 21, 13, 38 and 4 7-3(R)-4-(3-Ethyl-4-methyl-1H-pyrazol-5-yl)-6-(3- L RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 40, 21, 13, 38 and 4 7-4(R)-4-(3-(Methylamino)pyrrolidin-1-yl)-6-(2,4,5,6- L Solid isolatedtetrahydrocyclopenta[c]pyrazol-3-yl)pyrimidin-2-amine 41, 21, 42 and 4from deprotection dihydrochloride 38 absent step 7-5(R)-4-(2H-Indazol-3-yl)-6-(3-(methylamino)pyrrolidin- D Solid isolated1-yl)pyrimidin-2-amine dihydrochloride (Steps 2 and 3) from deprotection43 and 4 step 7-6 (R)-4-(3-Aminopyrrolidin-1-yl)-6-(3,4-dimethyl-1H- ISolid isolated pyrazol-5-yl)pyrimidin-2-amine dihydrochloride 44, 13 and45 from deprotection step 7-7(R)-4-(3-Aminopyrrolidin-1-yl)-6-(4-chloro-3-methyl-1H- I Solid isolatedpyrazol-5-yl)pyrimidin-2-amine dihydrochloride 46, 13 and 45 fromdeprotection step 7-8(R)-4-(3-Aminopyrrolidin-1-yl)-6-(3-ethyl-4-methyl-1H- L RP HPLCpyrazol-5-yl)pyrimidin-2-amine 40, 21, 13, 38 and 45 8-1(R)-4-(3-(Methylamino)pyrrolidin-1- C RP HPLCyl)-6-(1H-pyrazol-4-yl)pyrimidin-2-amine 4 and 47 HCI/dioxane used infinal step 8-2 (R)-4-(1-Methyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 48 8-3(R)-4-(1-Ethyl-1H-pyrazol-4-yl)-6-(3- D Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin- (Steps 2 and 3) fromdeprotection 2-amine dihydrochloride 49 and 4 step 8-4(R)-4-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 50 8-5(R)-4-(1-Cyclobutyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 51 HCI/dioxane usedin final step 8-6 (R)-4-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-6-(3- C RPHPLC (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 52 HCI/dioxaneused in final step 8-7 (R)-4-(3-(Methylamino)pyrrolidin-1- D Solidisolated yl)-6-(l-(trifluoromethyl)-1H-pyrazol-4- (Steps 2 and 3) fromdeprotection yl)pyrimidin-2-amine dihydrochloride 53 and 4 step 8-8(R)-4-(3-(Methylamino)pyrrolidin-1- D Solid isolatedyl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol- (Steps 2 and 3) fromdeprotection 4-yl)pyrimidin-2-amine dihydrochloride 54 and 4 step 8-9(R)-2-(4-(2-Amino-6-(3-(methylamino)pyrrolidin- C RP HPLC1-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol 4 and 55 8-10(R)-4-(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 56 8-11(R)-4-(3-(Methylamino)pyrrolidin-1-yl)-6-(1- C RP HPLC(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine 4 and 57 8-12(R)-3-(4-(2-Amino-6-(3-(methylamino)pyrrolidin- C RP HPLC1-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile 4 and 58 8-13(R)-2-(4-(2-amino-6-(3-(methylamino)pyrrolidin- C RP HPLC1-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile 4 and 59trifluoroacetate 8-14 Ethyl3-(4-(2-amino-6-((R)-3-(methylamino)pyrrolidin- C RP HPLC1-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)piperidine- 4 and 63 1-carboxylateK₂CO₃ used as base in Step 1 8-15(R)-4-(3-Aminopyrrolidin-1-yl)-6-(1-(trifluoromethyl)-1H- D Solidisolated pyrazol-4-yl)pyrimidin-2-amine dihydrochloride (Steps 2 and 3)from deprotection 53 and 45 step 8-164-(3-(Methylamino)azetidin-1-yl)-6-(1-(trifluoromethyl)- D Solidisolated 1H-pyrazol-4-yl)pyrimidin-2-amine ditrifluoroacetate (Steps 2and 3) from deprotection 53 and 65 step TFA/DCM used in Step 3 8-17(R)-4-(3-Aminopyrrolidin-1-yl)-6-(1-ethyl-1H-pyrazol-4- D Solid isolatedyl)pyrimidin-2-amine dihydrochloride (Steps 2 and 3) from deprotection49 and 45 step 8-18 (R)-4-(3-Aminopyrrolidin-1-yl)-6-(1-(2,2,2- D Solidisolated trifluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2- (Steps 2 and 3)from deprotection amine dihydrochloride 54 and 45 step 9-1(R)-4-(5-Methyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 68 9-2(R)-4-(5-Ethyl-1H-pyrazol-4-yl)-6-(3- E RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 72 K₂CO₃ used asbase in Step 1 9-3 (R)-4-(5-Isopropyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 73 K₂CO₃ used asbase in Step 1 9-4 (R)-4-(5-cyclopropyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 74ditrifluoroacetate 9-5 (R)-4-(5-(Difluoromethyl)-1H-pyrazol-4-yl)-6- ERP HPLC (3-(methylamino)pyrrolidin-1-yl)pyrimidin-2- 4 and 77 aminetrifluoroacetate DCM absent in Step 2 9-6(R)-4-(3-(Methylamino)pyrrolidin-1-yl)-6-(5- C RP HPLC(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-2- 4 and 78 amine 9-7(R)-4-(3-Aminopyrrolidin-1-yl)-6-(5-methyl-1H- C RP HPLCpyrazol-4-yl)pyrimidin-2-amine 45 and 68 10-1(R)-4-(3,5-Dimethyl-1H-pyrazol-4-yl)-6-(3- C RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 79 11-1(R)-4-(1,3-Dimethyl-1H-pyrazol-4-yl)-6-(3- M RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 80 11-2(R)-4-(3-Ethyl-1-methyl-1H-pyrazol-4-yl)-6-(3- D Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine (Steps 2 and 3) fromdeprotection dihydrochloride 81 and 4 step 11-3(R)-4-(3-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)-6-(3- D Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine (Steps 2 and 3) fromdeprotection dihydrochloride 82 and 4 step 11-4(R)-4-(1-Methyl-3-(trifluoromethyl)-1H-pyrazol- D Solid isolated4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin- (Steps 2 and 3) fromdeprotection 2-amine dihydrochloride 83 and 4 step 11-5(R)-4-(2-Amino-6-(3-(methylamino)pyrrolidin-1- D Solid isolatedyl)pyrimidin-4-yl)-1-methyl-1H-pyrazole-3- 84, 8 and 4 from deprotectioncarbonitrile dihydrochloride step 11-6(R)-4-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)- D Solid isolated6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 85, 8 and 4 fromdeprotection dihydrochloride step 11-7 Isomer 2: N RP HPLC4-(1,3-Dimethyl-1H-pyrazol-4-yl)-6-(3-methyl-3- 1, 80 and 88 followed by(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Chiral HPLC 11-8 Isomer1: O RP HPLC 4-(1,3-Dimethyl-1H-pyrazol-4-yl)-6-(octahydro- 89 and 90followed by 6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-2-amine Chiral SFC11-8 Isomer 2: O RP HPLC 4-(1,3-Dimethyl-1H-pyrazol-4-yl)-6-(octahydro-89 and 90 followed by 6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-2-amineChiral SFC 12-1 (R)-4-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-(3- E RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4 and 91 DCM absent inStep 2 12-2 (R)-4-(2-Amino-6-(3-(methylamino)pyrrolidin-1- D Solidisolated yl)pyrimidin-4-yl)-1-methyl-1H-pyrazole-5- 92, 8 and 4 fromdeprotection carbonitrile dihydrochloride step 12-3(R)-4-(1-(Difluoromethyl)-5-methyl-1H-pyrazol- D Solid isolated4-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin- 93, 8 and 4 fromdeprotection 2-amine dihydrochloride step 12-4(R)-4-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol- D Solid isolated3-yl)-6-(3-(methylamino)pyrrolidin-1- (Steps 2 and 3) from deprotectionyl)pyrimidin-2-amine dihydrochloride 94 and 4 step 13-1(R)-4-(3-(methylamino)pyrrolidin-1-yl)-6-(1,3,5- C RP HPLCtrimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine 4 and 95 14-1(R)-6-(1,5-Dimethyl-1H-pyrazol-4-yl)-4-(3- P Solid isolated(methylamino)pyrrolidin-1-yl)pyridin-2-amine 99 and 3 from deprotectiondihydrochloride step 15-1 (R)-4-(3-Ethyl-1H-pyrazol-5-yl)-6-(3- F Solidisolated (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 102, 13 and 4from deprotection dihydrochloride step 15-24-(3-(Methylamino)azetidin-1-yl)-6-(3- G RP HPLC(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2- 15, 16, 17 and 119 amine16-1 (S)-4-(4-Methyl-1H-pyrazol-5-yl)-6-(3- H RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 1, 19 and 103ditrifluoroacetate 16-2 4-(4-Methyl-1H-pyrazol-5-yl)-6-(3-methyl-3- H RPHPLC (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 1, 19 and 104ditrifluoroacetate HCI/dioxane used in final step 16-34-(4-Methyl-1H-pyrazol-5-yl)-6-(3- H RP HPLC(methylamino)azetidin-1-yl)pyrimidin- 1, 19 and 119 2-amineditrifluoroacetate 16-4 4-(3-Aminoazetidin-1-yl)-6-(4-methyl-1H- H RPHPLC pyrazol-5-yl)pyrimidin-2-amine 1, 19 and 105 ditrifluoroacetate16-5 4-(4-Methyl-1H-pyrazol-5-yl)-6-(3-methyl-3- H RP HPLC(methylamino)azetidin-1-yl)pyrimidin-2-amine 1, 19 and 106ditrifluoroacetate HCI/dioxane used in final step 16-64-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)- H RP HPLC6-(4-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine 1, 19 and 107 16-74-(4-Methyl-1H-pyrazol-5-yl)-6-((4aR,7aR)- H RP HPLCoctahydro-6H-pyrrolo[3,4-b]pyridin-6- 1, 19 and 108 yl)pyrimidin-2-amineditrifluoroacetate HCI/dioxane used in final step 16-8(R)-4-(4-(Difluoromethyl)-1H-pyrazol-5-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 111, 16, 17 and 3ditrifluoroacetate TFA and TfOH, microwave 80° C. used in final step16-9 (R)-4-(3-(Methylamino)pyrrolidin-1-yl)-6-(4- G RP HPLC(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2- 114, 16, 17 and 3 amineditrifluoroacetate TFA/DCM used in final step 16-10(R)-4-(4-Fluoro-1H-pyrazol-5-yl)-6-(3- I RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine (Step 3)ditrifluoroacetate 118 16-11 (R)-4-(3-aminopyrrolidin-1-yl)-6-(4-chloro-I Solid isolated 1H-pyrazol-5-yl)pyrimidin-2-amine 18 and 24 fromdeprotection dihydrochloride step 16-12(R)-4-(4-bromo-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 3, 16, 17 and 120 16-134-(4-bromo-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)azetidin-1-yl)pyrimidin-2-amine 3, 16, 17 and 119 16-14(R)-4-(3-(methylamino)pyrrolidin-1-yl)-6-(4- G RP HPLC(methylthio)-1H-pyrazol-3-yl)pyrimidin-2- 3, 16, 17 and 121 amine 17-14-(4,5-dimethyl-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)azetidin-1-yl)pyrimidin-2-amine 3, 16, 17 and 122 17-2(R)-4-(5-methyl-4-(trifluoromethyl)-1H-pyrazol- I RP HPLC3-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyrimidin- 4, 13, 124 2-amineditrifluoroacetate 17-3 (R)-4-(4-fluoro-5-methyl-1H-pyrazol-3-yl)-6-(3-G PR HPLC (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 3, 16, 17 and125 ditrifluoroacetate 17-4(S)-4-(4-chloro-3-methyl-1H-pyrazol-5-yl)-6-(3- G Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 16, 17, 103 and 126 fromdeprotection dihydrochloride step 17-54-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)azetidin-1-yl)pyrimidin-2-amine 16, 17, 119 and 126 17-64-(3-aminoazetidin-1-yl)-6-(4-chloro-5-methyl- G RP HPLC1H-pyrazol-3-yl)pyrimidin-2-amine ditrifluoroacetate 16, 17, 105 and 12617-7 4-(4-chloro-5-methyl-1H-pyrazol-3-yl)-6-((4aR,7aR)- G Solidisolated octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-2- 16, 17,108 and 126 from deprotection amine dihydrochloride step 17-8(R)-3-(2-amino-6-(3-(methylamino)pyrrolidin-1- G RP HPLCyl)pyrimidin-4-yl)-5-methyl-1H-pyrazol-4-ol 3, 16, 17 and 127 BBr₃ finalstep 17-9 (R)-4-(4-methoxy-5-methyl-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino) pyrrolidin-1-yl) pyrimidin-2-amine 3, 16, 17 and 127 BBr₃final step 17-10(R)-4-(3-(difluoromethyl)-4-methyl-1H-pyrazol-5-yl)-6-(3- H RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 1, 3 and 129ditrifluoroacetate 17-114-(3-(difluoromethyl)-4-methyl-1H-pyrazol-5-yl)-6-(3- H RP HPLC(methylamino)azetidin-1-yl)pyrimidin-2-amine 1, 119 and 129ditrifluoroacetate 17-12 (R)-4-(4-methyl-3-(trifluoromethyl)-1H-pyrazol-F Solid isolated 5-yl)-6-(3-(methylamino)pyrrolidin-1- 4, 13 and 131from deprotection yl)pyrimidin-2-amine dihydrochloride step 17-13(R)-4-(5-ethyl-4-fluoro-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 3, 16, 17 and 132ditrifluoroacetate 17-14 (R)-4-(3-chloro-4-methyl-1H-pyrazol-5-yl)-6-(3-F Solid isolated (methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 4, 13and 134 from deprotection dihydrochloride step 17-15(R)-4-(4,5-dichloro-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 3, 16, 17 and 135 17-164-(4,5-dichloro-1H-pyrazol-3-yl)-6-(3- G RP HPLC(methylamino)azetidin-1-yl)pyrimidin-2-amine 16, 17, 119 and 135 17-17(R)-4-(4-chloro-3-methoxy-1H-pyrazol-5-yl)-6-(3- G Solid isolated(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine 3, 16, 17 and 136 fromdeprotection dihydrochloride step 18-1(R)-6-(4-methyl-1H-pyrazol-5-yl)-4-(3- H RP HPLC(methylamino)pyrrolidin-1-yl)pyridin-2-amine 3, 19 and 98ditrifluoroacetate LCMS System Ex. and No. ¹H NMR Method LCMS data 1-11H NMR (400 MHz, DMSO-d6) δ 1.70-1.91 (m, 1H), 1.97-2.19 System 2 m/z260 (m, 1H), 2.33 (s, 3H), 2.94-3.78 (m, 5H), 5.95 (br. s, 2H), 6.28 (s,Method E (M + H)⁺ (ES⁺), 1H), 6.70 (s, 1H), 7.67 (br. s, 1H), 13.05 (br.s, 1H) at 1.69 min, One exchangeable proton not observed. 240 nm 1-2 1HNMR (400 MHz, DMSO-d6) δ 2.23-2.40 (m, 2H), 2.56-2.63 System 2 m/z 274(m, 3H), 3.64-3.73 (m, 1H), 3.81-3.96 (m, 4H), 4.06 (s, 3H), Method E(M + H)⁺ (ES⁺), 6.47 (s, 1H), 6.91 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 2.1Hz, 1H), at 2.01 min, 9.33-9.61 (m, 2H), 9.78 (br. s, 1H), 12.89 (br. s,1H) 202 nm One exchangeable proton not observed. 2-1 1H NMR (400 MHz,DMSO-d6) δ 1.65-1.84 (m, 1H), 1.93-2.09 System 3 m/z 274 (m, 1H), 2.29(s, 3H), 3.02-3.24 (m, 2H), 3.24-3.62 (m, 3H), Method D (M + H)⁺ (ES⁺),3.88 (s, 3H), 5.93 (br. s, 2H), 6.21 (s, 1H), 6.64 (d, J = 2.3 Hz, 1H),at 1.91 min, 7.70 (d, J = 2.2 Hz, 1H) 202 nm One exchangeable proton notobserved. 2-2 1H NMR (400 MHz, DMSO-d6) δ 2.25-2.44 (m, 2H), 2.56-2.65System 4 m/z 310 (m, 3H), 3.64-3.78 (m, 1H), 3.79-4.03 (m, 4H),6.83-6.89 (m, Method G (M + H)⁺ (ES⁺), 1H), 7.48-7.53 (m, 1H), 7.97 (t,J = 57.8 Hz, 1H), 8.51-8.56 at 2.32 min, (m, 1H), 9.29-9.87 (m, 2H),12.24-12.44 (m, 1H) 254 nm Two exchangeable protons not observed. 3-1 1HNMR (400 MHz, Methanol-d4) δ 1.81-2.02 (m, 1H), 2.16- System 3 m/z 2742.36 (m, 4H), 2.44 (s, 3H), 3.33-3.44 (m, 2H), 3.46-3.58 (m, Method D(M + H)⁺ (ES⁺), 1H), 3.59-3.83 (m, 2H), 6.34 (s, 1H), 6.57 (s, 1H) at1.99 min, Four exchangeable protons not observed. 240 nm 3-2 1H NMR (400MHz, DMSO-d6) δ 0.71-0.77 (m, 2H), 0.99-1.06 System 4 m/z 300 (m, 2H),1.96-2.05 (m, 1H), 2.31-2.42 (m, 1H), 2.55-2.64 (m, Method G (M + H)⁺(ES⁺), 4H), 3.78-3.96 (m, 5H), 6.59-6.64 (m, 1H), 6.85-6.90 (m, 1H), at2.45 min, 9.35-9.89 (m, 2H), 12.07-12.18 (m, 1H) 254 nm Threeexchangeable protons not observed. 3-3 ¹H NMR (400 MHz, Methanol-d₄) δ2.20-2.47 (m, 1H), 2.47- System 4 m/z 310 2.68 (m, 1H), 2.71-2.87 (m,3H), 3.78-4.20 (m, 5H), 6.71-6.79 Method G (M + H)⁺ (ES⁺), (m, 1H),6.87-7.21 (m, 1H), 7.29-7.41 (m, 1H). at 2.46 min, Four exchangeableprotons not observed. 254 nm 3-4 1H NMR (400 MHz, Methanol-d4) δ2.21-2.66 (m, 2H), 2.81 (s, System 2 m/z 328 3H), 3.70-4.16 (m, 5H),6.76 (s, 1H), 7.52 (s, 1H) Method E (M + H)⁺ (ES⁺), Six exchangeableprotons not observed. at 2.70 min, 243 nm 3-5 1H NMR (400 MHz,Methanol-d4) δ 1.76-1.99 (m, 1H), 2.07- System 2 m/z 314 2.34 (m, 1H),3.40-3.88 (m, 4H), 6.30 (s, 1H), 7.14 (s, 1H) Method E (M + H)⁺ (ES⁺),Five exchangeable protons not observed. at 2.60 min, One proton obscuredby solvent peak. 202 nm 4-1 1H NMR (400 MHz, Methanol-d4) δ 1.91-2.05(m, 1H), 2.24- System 2 m/z 274 2.35 (m, 4H), 2.49 (s, 3H), 3.40-3.83(m, 5H), 6.16 (s, 1H), 7.48 Method E (M + H)⁺ (ES⁺), (s, 1H) at 2.26min, Four exchangeable protons not observed. 241 nm 4-2 1H NMR (400 MHz,Methanol-d4) δ 1.22 (t, J = 7.5 Hz, 3H), System 4 m/z 288 1.83-1.97 (m,1H), 2.17-2.29 (m, 1H), 2.42 (s, 3H), 2.79 (q, Method G (M + H)⁺ (ES⁺),J = 7.5 Hz, 2H), 3.32-3.42 (m, 2H), 3.44-3.55 (m, 1H), at 3.21 min,3.57-3.81 (m, 2H), 6.12 (s, 1H), 7.48 (s, 1H) 254 nm Four exchangeableprotons not observed 4-3 1H NMR (400 MHz, Chloroform-d) δ 1.74-2.00 (m,1H), 2.10- System 4 m/z 294/296 2.25 (m, 1H), 2.49 (s, 3H), 3.00-3.93(m, 5H), 4.88 (br. s, 2H), Method G (M + H)⁺ (ES⁺), 6.57 (s, 1H),7.51-7.61 (m, 1H) at 2.51 min, Two exchangeable protons not observed.254 nm 4-4 1H NMR (400 MHz, Deuterium Oxide) δ 2.29-2.42 (m, 1H), 2.53-System 4 m/z 290 2.67 (m, 1H), 2.83 (s, 3H), 3.74-3.89 (m, 3H), 3.95 (s,3H), 4.02- Method G (M + H)⁺ (ES⁺), 4.11 (m, 2H), 6.61 (s, 1H), 7.68 (s,1H). at 2.15 min, Four exchangeable protons not observed. 254 nm 4-5 1HNMR (400 MHz, Methanol-d4) δ 1.76-1.94 (m, 1H), 2.15- System 2 m/z 2602.27 (m, 1H), 2.31 (s, 3H), 3.42-3.83 (m, 5H), 6.12 (s, 1H), 7.45 MethodE (M + H)⁺ (ES⁺), (s, 1H) at 1.90 min, Five exchangeable protons notobserved. 240 nm 5-1 1H NMR (400 MHz, Methanol-d4) δ 2.37 (s, 3H),2.45-2.64 (m, System 2 m/z 288 2H), 2.75-2.84 (m, 3H), 3.53-3.59 (m,1H), 3.63-3.72 (m, 1H), Method E (M + H)⁺ (ES⁺), 3.72-4.11 (m, 6H),6.53-6.58 (m, 1H), 6.78 (s, 1H) at 2.06 min, Five exchangeable protonsnot observed. 226 nm 5-2 1H NMR (400 MHz, DMSO-d6) δ 1.68-1.86 (m, 1H),1.92-2.10 System 3 m/z 324 (m, 1H), 2.29 (s, 3H), 2.44 (s, 3H),3.01-3.26 (m, 2H), 3.38-3.64 Method D (M + H)⁺ (ES⁺), (m, 3H), 6.07 (br.s, 2H), 6.23 (s, 1H), 6.68 (s, 1H), 7.85 at 2.59 min, (t, J = 57.9 Hz,1H) 240 nm One exchangeable proton not observed. 6-1 1H NMR (400 MHz,Methanol-d4) δ 1.85-2.01 (m, 1H), 2.19- System 2 m/z 288 2.32 (m, 4H),2.44 (s, 3H), 3.34-3.43 (m, 2H), 3.47-3.59 (m, Method E (M + H)⁺ (ES⁺),1H), 3.60-3.80 (m, 2H), 3.88 (s, 3H), 6.17 (s, 1H), 7.43 (s, 1H) at 2.21min, Three exchangeable protons not observed. 241 nm 6-2 1H NMR (400MHz, Methanol-d4) δ 1.84-2.00 (m, 1H), 2.20- System 3 m/z 324 2.35 (m,4H), 2.43 (s, 3H), 3.35-3.84 (m, 5H), 6.26 (s, 1H), 7.44 Method E (M +H)⁺ (ES⁺), (t, J = 59.8 Hz, 1H), 7.87 (s, 1H) at 2.60 min, Threeexchangeable protons not observed. 214 nm 7-1 ¹H NMR (400 MHz,Methanol-d₄) δ 2.18-2.30 (m, 6H), 2.32- System 4 m/z 288 2.69 (m, 2H),2.75-2.90 (m, 3H), 3.76-4.15 (m, 5H), 6.30-6.41 Method G (M + H)⁺ (ES⁺),(m, 1H) at 2.96 min, Six exchangeable protons not observed. 254 nm 7-21H NMR (400 MHz, Methanol-d4) δ 2.24-2.44 (m, 4H), 2.46- System 4 m/z308/310 2.65 (m, 1H), 2.77-2.86 (m, 3H), 3.73-4.15 (m, 5H), 6.80-6.89Method G (M + H)⁺ (ES⁺), (m, 1H) at 3.13 min, Four exchangeable protonsnot observed. 254 nm 7-3 1H NMR (400 MHz, Chloroform-d) δ 1.25 (t, J =7.6 Hz, 3H), System 4 m/z 302 1.82-1.93 (m, 1H), 2.13-2.21 (m, 1H), 2.23(s, 3H), 2.49 (s, 3H), Method G (M + H)⁺ (ES⁺), 2.65 (q, J = 7.6 Hz,2H), 3.21-3.75 (m, 5H), 4.78 (br. s, 2H), at 3.45 min, 6.02 (s, 1H) 254nm Two exchangeable protons not observed. 7-4 1H NMR (400 MHz,Methanol-d4) δ 2.22-2.54 (m, 1H), 2.55- System 4 m/z 300 2.75 (m, 3H),2.78-2.95 (m, 7H), 3.73-4.15 (m, 5H), 6.17-6.21 Method G (M + H)⁺ (ES⁺),(m, 1H) at 2.62 min, Six exchangeable protons not observed. 254 nm 7-51H NMR (400 MHz, Methanol-d4) δ 2.33-2.48 (m, 1H), 2.54- System 4 m/z310 2.71 (m, 1H), 2.85 (s, 3H), 3.75-4.18 (m, 5H), 6.65 (s, 1H), 7.32-Method G (M + H)⁺ (ES⁺), 7.51 (m, 1H), 7.57-7.68 (m, 1H), 7.82-7.94 (m,1H), 8.36-8.51 at 3.47 min, (m, 1H) 254 nm Six exchangeable protons notobserved. 7-6 ¹H NMR (400 MHz, Methanol-d₄) δ 2.26 (s, 3H), 2.30 (s,3H), System 4 m/z 274 2.44-2.67 (m, 2H), 3.82-3.95 (m, 3H), 4.02-4.12(m, 2H), 6.33, Method G (M + H)⁺ (ES⁺), 6.29 (2 × s, 1H). at 2.49 min,Seven exchangeable protons not observed. 254 nm 7-7 ¹H NMR (400 MHz,Methanol-d₄) δ 2.18-2.33 (m, 1H), 2.35 (s, System 4 m/z 294/296 3H),2.47-2.66 (m, 1H), 3.73-4.19 (m, 5H), 6.81, 6.86 (2 × s, Method G (M +H)⁺ (ES⁺), 1H). at 2.53 min, Seven exchangeable protons not observed.254 nm 7-8 1H NMR (400 MHz, Methanol-d4) δ 1.17-1.28 (m, 3H), 1.77-System 4 m/z 288 1.93 (m, 1H), 2.15-2.28 (m, 4H), 2.61-2.71 (m, 2H),3.17-3.30 Method G (M + H)⁺ (ES⁺), (m, 1H), 3.44-3.58 (m, 1H), 3.60-3.81(m, 3H), 6.11 (s, 1H) at 2.91 min, Five exchangeable protons notobserved 254 nm 8-1 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.83 (m, 1H),1.94-2.09 System 2 m/z 260 (m, 1H), 2.29 (s, 3H), 3.09-3.25 (m, 2H),3.38-3.64 (m, 3H), Method E (M + H)⁺ (ES⁺), 5.84 (br. s, 2H), 6.04 (s,1H), 7.77-8.37 (m, 2H), 12.98 (br. s, 1H) at 1.70 min, One exchangeableproton not observed. 239 nm 8-2 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.83(m, 1H), 1.94-2.09 System 2 m/z 274 (m, 1H), 2.29 (s, 3H), 3.07-3.26 (m,2H), 3.36-3.60 (m, 3H), Method E (M + H)⁺ (ES⁺), 3.85 (s, 3H), 5.83 (br.s, 2H), 5.99 (s, 1H), 7.88 (s, 1H), at 1.85 min, 8.13 (s, 1H) 202 nm Oneexchangeable proton not observed. 8-3 1H NMR (400 MHz, Methanol-d4) δ1.49-1.55 (m, 3H), 2.22- System 4 m/z 288 2.66 (m, 2H), 2.78-2.85 (m,3H), 3.73-4.13 (m, 5H), 4.24-4.33 Method G (M + H)⁺ (ES⁺), (m, 2H),6.49-6.56 (m, 1H), 8.15-8.18 (m, 1H), 8.48-8.54 (m, at 2.24 min, 1H) 254nm Five exchangeable protons not observed. 8-4 1H NMR (400 MHz, DMSO-d6)δ 0.91-1.10 (m, 4H), 1.65-1.83 System 2 m/z 300 (m, 1H), 1.93-2.09 (m,1H), 2.29 (s, 3H), 3.06-3.59 (m, 5H), Method E (M + H)⁺ (ES⁺), 3.68-3.80(m, 1H), 5.83 (br. s, 2H), 6.02 (s, 1H), 7.87 (s, 1H), at 2.09 min, 8.23(s, 1H) 202 nm One exchangeable proton not observed. 8-5 1H NMR (400MHz, Methanol-d4) δ 1.81-2.00 (m, 3H), 2.16- System 2 m/z 314 2.30 (m,1H), 2.38-2.64 (m, 7H), 3.29-3.42 (m, 3H), 3.45-3.80 Method E (M + H)⁺(ES⁺), (m, 3H), 6.12 (s, 1H), 8.00 (s, 1H), 8.21 (s, 1H) at 2.38 min,Three exchangeable protons not observed. 202 nm 8-6 1H NMR (400 MHz,DMSO-d6) δ 1.65-2.13 (m, 3H), 2.30 (s, 3H), System 2 m/z 310 3.13-3.25(m, 2H), 3.39-3.66 (m, 3H), 5.95 (br. s, 2H), 6.18 (s, Method E (M + H)⁺(ES⁺), 1H), 7.84 (t, J = 59.1 Hz, 1H), 8.25 (s, 1H), 8.67 (s, 1H) at2.26 min, 202 nm 8-7 1H NMR (400 MHz, DMSO-d6) δ 2.19-2.45 (m, 2H),2.56-2.66 System 4 m/z 328 (m, 3H), 3.61-3.73 (m, 1H), 3.76-4.02 (m,4H), 6.74-6.87 (m, Method G (M + H)⁺ (ES⁺), 1H), 8.80-8.90 (m, 1H),9.21-9.69 (m, 3H), 13.40-13.57 (m, at 2.74 min, 1H) 254 nm Twoexchangeable proton not observed. 8-8 1H NMR (400 MHz, Methanol-d4) δ2.19-2.67 (m, 2H), 2.79- System 4 m/z 342 2.86 (m, 3H), 3.74-4.13 (m,5H), 5.06-5.16 (m, 2H), 6.54-6.62 Method G (M + H)⁺ (ES⁺), (m, 1H),8.24-8.27 (m, 1H), 8.58-8.63 (m, 1H) at 2.54 min, Five exchangeableprotons not observed. 254 nm 8-9 1H NMR (400 MHz, Methanol-d4) δ1.82-2.03 (m, 1H), 2.18- System 2 m/z 304 2.32 (m, 1H), 2.43-2.49 (m,3H), 3.33-3.56 (m, 3H), 3.58-3.78 Method E (M + H)⁺ (ES⁺), (m, 2H), 3.91(t, J = 5.3 Hz, 2H), 4.26 (t, at 1.69 min, J = 5.3 Hz, 2H), 6.11 (s,1H), 8.01 (s, 1H), 8.18 (s, 1H) 242 nm Four exchangeable protons notobserved. 8-10 1H NMR (400 MHz, DMSO-d6) δ 1.70-1.87 (m, 1H), 1.95-2.14System 2 m/z 318 (m, 1H), 2.33 (s, 3H), 3.18-3.26 (m, 4H), 3.39-3.57 (m,4H), Method E (M + H)⁺ (ES⁺), 3.69 (t, J = 5.2 Hz, 2H), 4.27 (t, J = 5.2Hz, 2H), at 1.96 min, 5.86 (br. s, 2H), 6.01 (s, 1H), 7.92 (s, 1H), 8.14(s, 1H) 254 nm One exchangeable proton not observed. 8-11 1H NMR (400MHz, Methanol-d4) δ 1.84-2.01 (m, 1H), 2.17- System 2 m/z 316 2.33 (m,1H), 2.46 (s, 3H), 3.33-3.80 (m, 5H), 4.99-5.12 (m, Method E (M + H)⁺(ES⁺), 4H), 5.52-5.66 (m, 1H), 6.14 (s, 1H), 8.10 (s, 1H), 8.28 (s, 1H)at 1.84 min, Three exchangeable protons not observed. 202 nm 8-12 1H NMR(400 MHz, Methanol-d4) δ 2.01-2.15 (m, 1H), 2.30- System 2 m/z 313 2.45(m, 1H), 2.61 (s, 3H), 3.07 (t, J = 6.4 Hz, 2H), 3.51-3.74 (m, Method E(M + H)⁺ (ES⁺), 4H), 3.76-3.85 (m, 1H), 4.48 (t, J = 6.4 Hz, 2H), 6.19(s, 1H), 8.07 at 1.89 min, (s, 1H), 8.26 (s, 1H) 240 nm Threeexchangeable protons not observed. 8-13 1H NMR (400 MHz, Methanol-d4) δ2.17-2.43 (m, 1H), 2.45- System 2 m/z 299 2.68 (m, 1H), 2.82 (s, 3H),3.71-4.12 (m, 5H), 5.47 (s, 2H), 6.53 Method E (M + H)⁺ (ES⁺), (s, 1H),8.23 (s, 1H), 8.53 (s, 1H) at 1.88 min, Three exchangeable protons notobserved. 202 nm 8-14 1H NMR (400 MHz, DMSO-d6) δ 1.11-1.26 (m, 3H),1.44-1.63 System 2 m/z 415 (m, 1H), 1.72-1.83 (m, 2H), 1.94-2.21 (m,3H), 2.29 (s, 3H), Method E (M + H)⁺ (ES⁺), 2.83-2.99 (m, 1H), 3.09-3.26(m, 3H), 3.41-3.62 (m, 3H), 3.84- at 2.59 min, 3.95 (m, 1H), 3.99-4.31(m, 4H), 5.84 (br. s, 2H), 6.03 (s, 1H), 202 nm 7.95 (s, 1H), 8.26 (s,1H) One exchangeable proton not observed. 8-15 1H NMR (400 MHz,Methanol-d4) δ 2.12-2.69 (m, 2H), 3.76- System 4 m/z 314 4.21 (m, 5H),6.66-6.72 (m, 1H), 8.45-8.50 (m, 1H), 9.01-9.08 Method G (M + H)⁺ (ES⁺),(m, 1H) at 2.40 min, Six exchangeable protons not observed. 254 nm 8-161H NMR (400 MHz, Methanol-d4) δ 2.78 (s, 3H), 4.22-4.51 (m, System 4 m/z314 3H), 4.53-4.73 (m, 2H), 6.51 (s, 1H), 8.39-8.49 (m, 1H), 8.98-Method G (M + H)⁺ (ES⁺), 9.08 (m, 1H) at 2.66 min, Five exchangeableprotons not observed. 254 nm 8-17 1H NMR (400 MHz, Methanol-d4) δ 1.52(t, J = 7.3 Hz, 3H), System 4 m/z 274 2.12-2.38 (m, 1H), 2.40-2.64 (m,1H), 3.74-3.95 (m, 3H), 3.97-4.18 Method G (M + H)⁺ (ES⁺), (m, 2H), 4.28(q, J = 7.3 Hz, 2H), 6.49-6.54 (m, 1H), 8.17-8.21 at 1.93 min, (m, 1H),8.51-8.58 (m, 1H) 254 nm Six exchangeable protons not observed. 8-18 1HNMR (400 MHz, Methanol-d4) δ 2.13-2.36 (m, 1H), 2.42- System 4 m/z 3282.67 (m, 1H), 3.73-3.97 (m, 3H), 3.98-4.20 (m, 2H), 5.06-5.16 Method G(M + H)⁺ (ES⁺), (m, 2H), 6.54-6.59 (m, 1H), 8.23-8.27 (m, 1H), 8.57-8.63(m, at 2.22 min, 1H) 254 nm Six exchangeable protons not observed. 9-11H NMR (400 MHz, Methanol-d4) δ 1.81-1.99 (m, 1H), System 2 m/z 2742.17-2.30 (m, 1H), 2.43 (s, 3H), 2.52 (s, 3H), 3.33-3.39 (m, 2H), MethodE (M + H)⁺ (ES⁺), 3.42-3.55 (m, 1H), 3.56-3.80 (m, 2H), 5.96 (s, 1H),7.91 (s, 1H) at 2.73 min, Four exchangeable protons not observed. 244 nm9-2 1H NMR (400 MHz, Methanol-d4) δ 1.26 (t, J = 7.6 Hz, 3H), System 2m/z 288 1.83-1.99 (m, 1H), 2.16-2.32 (m, 1H), 2.44 (s, 3H), 3.00 (q,Method E (M + H)⁺ (ES⁺), J = 7.6 Hz, 2H), 3.33-3.41 (m, 2H), 3.44-3.55(m, 1H), at 2.88 min, 3.57-3.84 (m, 2H), 5.96 (s, 1H), 7.89 (s, 1H) 202nm Four exchangeable protons not observed. 9-3 1H NMR (400 MHz,Methanol-d4) δ 1.24-1.39 (m, 6H), 1.83- System 3 m/z 302 2.02 (m, 1H),2.17-2.35 (m, 1H), 2.45 (s, 3H), 3.34-3.86 (m, Method D (M + H)⁺ (ES⁺),6H), 5.94 (s, 1H), 7.82 (s, 1H) at 2.25 min, Four exchangeable protonsnot observed. 254 nm 9-4 1H NMR (400 MHz, Methanol-d4) δ 0.84-0.97 (m,2H), 1.06- System 3 m/z 300 1.18 (m, 2H), 2.03-2.18 (m, 1H), 2.20-2.43(m, 1H), 2.44-2.68 Method E (M + H)⁺ (ES⁺), (m, 1H), 2.77-2.86 (m, 3H),3.71-4.11 (m, 5H), 6.42-6.56 (m, at 2.08 min, 1H), 8.06 (s, 1H) 214 nmSix exchangeable protons not observed. 9-5 1H NMR (400 MHz, Methanol-d4)δ 2.23-2.43 (m, 1H), 2.46- System 2 m/z 310 2.66 (m, 1H), 2.80 (s, 3H),3.62-4.16 (m, 5H), 6.43 (s, 1H), 7.02 Method E (M + H)⁺ (ES⁺), (t, J =53.7 Hz, 1H), 8.34 (s, 1H) at 2.05 min, Six exchangeable protons notobserved. 202 nm 9-6 1H NMR (400 MHz, DMSO-d6) δ 1.67-1.85 (m, 1H),1.93-2.09 System 3 m/z 328 (m, 1H), 2.28 (s, 3H), 3.12-3.27 (m, 2H),3.38-3.68 (m, 3H), Method D (M + H)⁺ (ES⁺), 5.85-5.97 (m, 3H), 8.29 (s,1H), 12.88-14.45 (br. s, 1 H) at 2.36 min, One exchangeable proton notobserved. 202 nm 9-7 1H NMR (400 MHz, Methanol-d4) δ 1.80-1.94 (m, 1H),2.14- System 2 m/z 260 2.29 (m, 1H), 2.52 (s, 3H), 3.40-3.84 (m, 5H),5.96 (s, 1H), 7.92 Method E (M + H)⁺ (ES⁺), (s, 1H) at 2.56 min, Fiveexchangeable protons not observed. 202 nm 10-1 1H NMR (400 MHz,Methanol-d4) δ 1.87-2.00 (m, 1H), 2.21- System 3 m/z 288 2.41 (m, 7H),2.47 (s, 3H), 3.35-3.57 (m, 3H), 3.58-3.80 (m, Method D (M + H)⁺ (ES⁺),2H), 5.84 (s, 1H) at 1.94 min, Four exchangeable protons not observed.242 nm 11-1 1H NMR (400 MHz, DMSO-d6) δ 1.66-1.82 (m, 1H), 1.94-2.09System 3 m/z 288 (m, 1H), 2.30 (s, 3H), 2.39 (s, 3H), 3.04-3.25 (m, 2H),3.38-3.58 Method D (M + H)⁺ (ES⁺), (m, 3H), 3.76 (s, 3H), 5.72-5.89 (m,3H), 8.03 (s, 1H) at 2.01 min, One exchangeable proton not observed. 245nm 11-2 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.25 (m, 3H), 2.17-2.46 System4 m/z 302 (m, 2H), 2.55-2.65 (m, 3H), 2.78-2.90 (m, 2H), 3.61-3.72 (m,Method G (M + H)⁺ (ES⁺), 1H), 3.76-3.94 (m, 7H), 6.07-6.10 (m, 1H), 8.43(s, 1H), 9.27- at 2.38 min, 9.69 (m, 2H), 12.62 (br. s, 1H) 254 nm Twoexchangeable protons not observed. 11-3 1H NMR (400 MHz, DMSO-d6) δ0.76-0.87 (m, 2H), 0.94-1.03 System 4 m/z 314 (m, 2H), 2.03-2.16 (m,1H), 2.24-2.45 (m, 2H), 2.56-2.65 (m, Method G (M + H)⁺ (ES⁺), 3H),3.62-3.74 (m, 1H), 3.78-3.97 (m, 7H), 6.41 (s, 1H), 8.49 (s, at 2.47min, 1H), 9.21-9.71 (m, 2H), 12.77 (br. s, 1H) 254 nm Two exchangeableproton not observed. 11-4 1H NMR (400 MHz, DMSO-d6) δ 2.25-2.44 (m, 2H),2.53-2.62 System 4 m/z 342 (m, 3H), 3.54-3.96 (m, 5H), 4.02 (s, 3H),6.12-6.22 (m, 1H), Method G (M + H)⁺ (ES⁺), 8.61-8.67 (m, 1H), 9.46-9.69(m, 2H), 9.87-9.99 (m, 1H), at 2.72 min, 13.09-13.21 (m, 1H) 254 nm Oneexchangeable proton not observed. 11-5 1H NMR (400 MHz, DMSO-d6) δ2.23-2.44 (m, 2H), 2.56-2.65 System 4 m/z 299 (m, 3H), 3.58-3.72 (m,1H), 3.73-3.96 (m, 4H), 4.05 (s, 3H), Method G (M + H)⁺ (ES⁺), 6.48 (s,1H), 8.73 (s, 1H), 9.08-9.62 (m, 2H), 13.20 (br. s, 1H) at 2.35 min, Twoexchangeable protons not observed. 254 nm 11-6 1H NMR (400 MHz, DMSO-d6)δ 2.22-2.45 (m, 2H), 2.58-2.66 System 4 m/z 324 (m, 3H), 3.63-3.75 (m,1H), 3.78-3.99 (m, 4H), 6.30 (s, 1H), Method G (M + H)⁺ (ES⁺), 7.91 (t,J = 59.0 Hz, 1H), 8.89 (s, 1H), 9.18-9.67 (m, 2H), at 2.46 min, 12.81(br. s, 1H) 254 nm Two exchangeable protons not observed and aromaticCH3 under DMSO peak. 11-7 1H NMR (400 MHz, Methanol-d4) δ 1.31 (s, 3H),1.86-2.00 (m, System 2 m/z 302 1H), 2.01-2.14 (m, 1H), 2.38 (s, 3H),2.44 (s, 3H), 3.34-3.70 (m, Method E (M + H)⁺ (ES⁺), 4H), 3.85 (s, 3H),5.92 (s, 1H), 7.92 (s, 1H) at 2.92 min, Three exchangeable protons notobserved. 202 nm 11-8 1H NMR (400 MHz, Methanol-d4) δ 1.46-1.57 (m, 1H),1.60- System 3 m/z 314 1.71 (m, 1H), 1.74-1.86 (m, 2H), 2.37-2.50 (m,4H), 2.59-2.72 Method D (M + H)⁺ (ES⁺), (m, 1H), 2.89-3.01 (m, 1H),3.38-3.72 (m, 5H), 3.85 (s, 3H), at 2.33 min, 5.94 (s, 1H), 7.92 (s, 1H)254 nm Three exchangeable protons not observed. 11-8 1H NMR (400 MHz,Methanol-d4) δ 1.43-1.56 (m, 1H), 1.60- System 3 m/z 314 1.71 (m, 1H),1.72-1.86 (m, 2H), 2.30-2.53 (m, 4H), 2.57-2.73 Method D (M + H)⁺ (ES⁺),(m, 1H), 2.84-3.02 (m, 1H), 3.34-3.73 (m, 5H), 3.85 (s, 3H), at 2.32min, 5.93 (s, 1H), 7.91 (s, 1H) 254 nm Three exchangeable protons notobserved. 12-1 1H NMR (400 MHz, Methanol-d4) δ 1.92-2.07 (m, 1H), 2.24-System 2 m/z 288 2.39 (m, 1H), 2.49-2.60 (m, 6H), 3.42-3.59 (m, 3H),3.61-3.80 Method E (M + H)⁺ (ES⁺), (m, 2H), 3.83 (s, 3H), 5.97 (s, 1H),7.78 (s, 1H) at 1.94 min, Three exchangeable protons not observed. 213nm 12-2 1H NMR (400 MHz, DMSO-d6) δ 2.21-2.46 (m, 2H), 2.55-2.65 System4 m/z 299 (m, 3H), 3.73-4.03 (m, 5H), 4.13 (s, 3H), 6.47 (s, 1H), 8.49(s, Method G (M + H)⁺ (ES⁺), 1H), 9.15-9.75 (m, 2H), 13.28 (br. s, 1H)at 2.31 min, Two exchangeable protons not observed. 254 nm 12-3 1H NMR(400 MHz, DMSO-d6) δ 2.19-2.46 (m, 2H), 2.56-2.63 System 4 m/z 324 (m,3H), 2.66 (s, 3H), 3.61-3.73 (m, 1H), 3.77-3.98 (m, 4H), Method G (M +H)⁺ (ES⁺), 6.23-6.35 (m, 1H), 7.99 (t, J = 57.2 Hz, 1H), 8.24 (s, 1H),at 2.54 min, 9.27-9.78 (m, 2H), 12.84 (br. s, 1H) 254 nm Twoexchangeable protons not observed. 12-4 1H NMR (400 MHz, DMSO-d6) δ2.20-2.44 (m, 2H), 2.56-2.71 System 4 m/z 300 (m, 5H), 3.15-3.26 (m,2H), 3.61-3.73 (m, 1H), 3.74-3.96 (m, Method G (M + H)⁺ (ES⁺), 4H),4.12-4.23 (m, 2H), 5.96-6.03 (m, 1H), 8.35 (s, 1H), 9.18- at 2.20 min,9.43 (m, 1H), 9.54 (br. s, 1H), 12.75 (br. s, 1H) 254 nm Twoexchangeable protons not observed. 13-1 1H NMR (400 MHz, Methanol-d4) δ1.83-2.00 (m, 1H), 2.17- System 2 m/z 302 2.31 (m, 4H), 2.37 (s, 3H),2.43 (s, 3H), 3.32-3.41 (m, 2H), 3.43- Method E (M + H)⁺ (ES⁺), 3.53 (m,1H), 3.55-3.81 (m, 5H), 5.78 (s, 1H) at 2.03 min, Three exchangeableprotons not observed. 202 nm 14-1 1H NMR (400 MHz, Methanol-d4) δ2.29-2.38 (m, 1H), 2.49 (s, System 4 m/z 287 3H), 2.52-2.62 (m, 1H),2.82 (s, 3H), 3.88 (s, 3H), 3.83-3.98 (m, Method G (M + H)⁺ (ES⁺), 4H),4.00-4.08 (m, 1H), 5.78 (d, J = 2.3 Hz, 1H), 6.24 at 2.76 min, (d, J =2.2 Hz, 1H), 7.75 (s, 1H) 254 nm Five exchangeable protons not observed.15-1 1H NMR (400 MHz, Methanol-d4) δ 2.23-2.30 (m, 5H), 2.37- System 4m/z 288 2.52 (m, 2H), 2.55-2.68 (m, 1H), 2.83-2.91 (m, 2H), 3.73-4.14Method G (M + H)⁺ (ES⁺), (m, 5H), 5.49 (s, 1H), 6.33 (s, 1H) at 2.71min, 254 nm 15-2 1H NMR (400 MHz, Methanol-d4) δ 2.37 (s, 3H), 3.65-3.74(m, System 2 m/z 314 1H), 3.79-3.87 (m, 2H), 4.22-4.30 (m, 2H), 6.17 (s,1H), 7.12 (s, Method E (M + H)⁺ (ES⁺), 1H) at 2.60 min, 243 nm 16-1 1HNMR (400 MHz, Methanol-d4) δ 2.23-2.42 (m, 1H), 2.36 (s, System 2 m/z274 3H), 2.46-2.66 (m, 1H), 2.82 (s, 3H), 3.76-3.93 (m, 2H), 3.96-Method E (M + H)⁺ (ES⁺), 4.12 (m, 3H), 6.33 (s, 1H), 7.67 (s, 1H) at2.01 min, 241 nm 16-2 1H NMR (400 MHz, Methanol-d4) δ 1.59 (d, J = 7.0Hz, 3H), 2.24- System 1 m/z 288 2.44 (m, 1H), 2.37 (d, J = 5.9 Hz, 3H),2.46-2.55 (m, 1H), 2.77 Method I (M + H)⁺ (ES⁺), (d, J = 8.3 Hz, 3H),3.78-4.12 (m, 4H), 6.32 at 1.88 min, (d, J = 3.9 Hz, 1H), 7.67 (s, 1H)240 nm 16-3 1H NMR (400 MHz, Methanol-d4) δ 2.34 (s, 3H), 2.79 (s, 3H),System 2 m/z 260 4.19-4.52 (m, 3H), 4.53-4.75 (m, 2H), 6.16 (s, 1H),7.66 (s, 1H) Method E (M + H)⁺ (ES⁺), at 2.05 min, 202 nm 16-4 1H NMR(400 MHz, Methanol-d4) δ 2.34 (s, 3H), 4.22-4.43 (m, System 2 m/z 2463H), 4.53-4.76 (m, 2H), 6.16 (s, 1H), 7.66 (s, 1H) Method E (M + H)⁺(ES⁺), at 1.92 min, 202 nm 16-5 1H NMR (400 MHz, Methanol-d4) δ 1.74 (s,3H), 2.34 (s, 3H), System 2 m/z 274 2.79 (s, 3H), 4.20-4.61 (m, 4H),6.17 (s, 1H), 7.67 (s, 1H) Method E (M + H)⁺ (ES⁺), at 2.15 min, 240 nm16-6 1H NMR (400 MHz, DMSO-d6) δ 1.73-1.78 (m, 1H), 1.98-2.03 System 3m/z 286 (m, 1H), 2.29 (s, 3H), 2.59-2.67 (m, 1H), 2.74-2.89 (m, 2H),Method J (M + H)⁺ (ES⁺), 2.90-3.00 (m, 1H), 3.16-3.92 (m, 5H), 4.07-4.48(m, 1H), 5.87 at 4.46 min, (s, 1H), 5.94 (s, 1H), 6.12 (s, 1H), 7.43 (s,1H) 304 nm 16-7 1H NMR (400 MHz, Methanol-d4) δ 1.77-2.06 (m, 4H), 2.37(s, System 3 m/z 300 3H), 2.78-3.02 (m, 1H), 3.02-3.15 (m, 1H),3.35-3.46 (m, 1H), Method J (M + H)⁺ (ES⁺), 3.59-3.76 (m, 1H), 3.84-4.20(m, 4H), 6.32 (d, J = 14.3 Hz, 1H), at 3.76 min, 7.67 (s, 1H) 254 nm16-8 1H NMR (400 MHz, Methanol-d4) δ 2.20-2.36 (m, 1H), 2.45- System 2m/z 308 2.59 (m, 1H), 2.79 (s, 3H), 3.62-3.89 (m, 3H), 3.89-4.05 (m,Method E (M − H)⁻ (ES⁻), at 2H), 6.49 (s, 1H), 7.37 (t, J = 55.4 Hz,1H), 8.08 (s, 1H) 2.27 min, 238 nm 16-9 1H NMR (400 MHz, Methanol-d4) δ2.21-2.43 (m, 1H), 2.47- System 2 m/z 328 2.65 (m, 1H), 2.81 (s, 3H),3.72-3.89 (m, 2H), 3.93-4.11 (m, Method E (M + H)⁺ (ES⁺), 3H), 6.47 (s,1H), 8.43 (s, 1H) at 2.33 min, 236 nm 16-10 1H NMR (400 MHz, DeuteriumOxide) δ 2.27-2.47 (m, 1H), 2.52- System 4 m/z 278 2.68 (m, 1H), 2.84(s, 3H), 3.77-3.95 (m, 2H), 3.97-4.16 (m, Method G (M + H)⁺ (ES⁺), 3H),6.53 (s, 1H), 7.84 (d, J = 4.4 Hz, 1H) at 2.26 min, 254 nm 16-11 1H NMR(400 MHz, Methanol-d4) δ 2.16-2.36 (m, 1H), 2.42- System 4 m/z 280 2.65(m, 1H), 3.49-4.20 (m, 5H), 6.82 (s, 1H), 8.01 (s, 1H) Method G (M + H)⁺(ES⁺), at 2.14 min, 254 nm 16-12 ¹H NMR (400 MHz, Methanol-d4) δ 1.96(brs, 1H), 2.28 (brs, 1H), System 3 m/z 338/340 2.46 (s, 3H), 3.33-3.41(m, 2H), 3.54 (brs, 1H), 3.67-3.76 (m, 2H), Method K (M + H)⁺ (ES⁺),6.57 (s, 1H), 7.71 (s, 1H) at 4.49 min, 240 nm 16-13 ¹H NMR (400 MHz,Methanol-d4) δ 2.38 (s, 3H), 3.70-3.75 (m, System 2 m/z 324/326 1H),3.83-3.86 (m, 2H), 4.26-4.30 (m, 2H), 6.42 (s, 1H), 7.70 (brs, Method E(M + H)⁺ (ES⁺), 1H) at 2.18 min, 215 nm 16-14 1H NMR (400 MHz,Methanol-d4) δ 1.95 (1H, s), 2.27 (1H, s), System 1 m/z 306 2.41 (3H,s), 2.45 (3H, s), 3.39 (2H, m), 3.51-3.54 (1H, s), 3.68- Method I (M +H)⁺ (ES⁺), 3.75 (2H, m), 6.72(1H, s), 7.66(1H, s) at 2.14 min, 220 nm17-1 1H NMR (400 MHz, Methanol-d4) δ 2.24 (s, 6H), 2.39 (s, 3H), System2 m/z 274 3.73 (brs, 1H), 3.85 (t, J = 4.8 Hz, 2H), 4.29 (t, Method E(M + H)⁺ (ES⁺), J = 7.2 Hz, 2H), 6.01 (brs, 1H) at 2.12 min, 241 nm 17-21H NMR (400 MHz, Methanol-d4) δ 2.24-2.64 (m, 5H), 2.80 (s, System 4 m/z342 3H), 3.70-4.10 (m, 5H), 6.43 (s, 1H) Method G (M + H)⁺ (ES⁺), at2.99 min, 254 nm 17-3 1H NMR (400 MHz, DMSO-d6 + Deuterium Oxide) δ 2.30(s, 3H), System 2 m/z 292 2.39 (brs, 2H), 2.66 (s, 3H), 3.85-3.72 (m,3H), 3.93 (brs, 2H), Method E (M + H)⁺ (ES⁺), 6.31 (s, 1H) at 2.16 min,239 nm 17-4 1H NMR (400 MHz, Methanol-d4) δ 2.24-2.64 (m, 5H), 2.80 (s,System 4 m/z 308 3H), 3.70-4.10 (m, 5H), 6.43 (s, 1H) Method G (M +H)⁺(ES⁺), at 2.29 min, 254 nm 17-5 1H NMR (400 MHz, DMSO-d6) δ 2.10 (s,3H), 2.66 (s, 3H), 4-1-4-3 System 2 m/z 294 (m, 2H), 4.44 (m, 2H), 4.61(s, 1H), 6.50 (s, 1H), 7.31 (brs, 1H), Method E (M + H)⁺ (ES⁺), 8.47(brs, 1H), 9.75(brs, 1H), 11.98(brs, 1H), 14.13 (s, 1H) at 2.35 min, 241nm 17-6 1H NMR (400 MHz, DMSO-d6) δ 14.10 (s, 1H), 11.95 (s, 1H), 8.48System 2 m/z 280 (s, 3H), 7.29 (s, 1H), 6.49 (s, 1H), 4.61 (s, 1H), 4.45(s, 1H), 4.1-4.3 Method E (M + H)⁺ (ES⁺), (m, 3H), 2.32 (s, 3H). at 2.09min, 202 nm 17-7 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.77 (m, 5H), 2.32 (s,3H) System 4 m/z 334 2.79-2.91 (m, 2H), 3.22-3.14 (m, 1H), 3.62-4.05 (m,4H), 6.63 Method G (M + H)⁺ (ES⁺), (s, 1H), 7.46 (s, 1H), 8.42 (s, 1H),9.10-9.30 (m, 1H), 10.06 (s, at 2.96 min, 1H), 11.99 (s, 1H), 14.23 (s,1H). 254 nm 17-8 1H NMR (400 MHz, Methanol-d4 ) 1.97 (brs, 1H), 2.22 (s,3H), System 2 m/z 290 2.30(m, 1H), 2.48(s, 3H), 3.2-3.8 (m, 5H) 6.29 (s,1H) Method E (M + H)⁺ (ES⁺), at 1.95 min, 202 nm 17-9 1H NMR (400 MHz,DMSO-d6) δ 1.78 (s, 1H), 2.02 (s, 1H), 2.14 (s, System 2 m/z 304 3H),2.28 (s, 3H), 3.20-3.58 (m, 5H), 3.73 (s, 3H), 5.86 (s, 2H), Method E(M + H)⁺ (ES⁺), 6.19 (s, 1H), 12.45 (s, 1H) at 2.03 min, 202 nm 17-10 1HNMR (400 MHz, Methanol-d4) δ 2.33-2.34 (m, 1H), 2.43 (s, System 2 m/z324 3H), 2.61 (brs, 1H), 2.85 (s, 3H), 3.89-4.08 (m, 5H), 6.38 (s, 1H),Method E (M + H)⁺ (ES⁺), 6.77 (t, J = 55.2 Hz, 1H) at 2.51 min, 245 nm17-11 1H NMR (400 MHz, Methanol-d4) δ 2.35 (s, 3H), 2.81 (s, 3H), System2 m/z 310 4.28-4.33 (m, 1H), 4.42 (brs, 2H), 4.66 (brs, 2H), 6.23 (s,1H), 7.08 Method E (M + H)⁺ (ES⁺), (t, J = 53.4 Hz, 1H) at 2.13 min, 245nm 17-12 1H NMR (400 MHz, Methanol-d4) δ 2.16-2.36 (m, 3H), 2.42- System4 m/z 341 2.67 (m, 2H), 3.65 (s, 3H), 3.71-4.20 (m, 5H), 6.85 (s, 1H)Method G (M + H)⁺ (ES⁺), at 3.26 min, 254 nm 17-13 1H NMR (400 MHz,DMSO-d6) δ 13.76 (s, 1H), 11.99 (s, 1H), 9.07 System 2 m/z 304 (s, 1H),8.96 (s, 1H), 8.39 (s, 1H), 7.21 (s, 1H), 6.32 (d, J = 10.9 Hz, Method E(M + H)⁺ (ES⁺), 1H), 3.91-3.71 (m, 6H), 2.70 (dd, J = 17.5, 8.9 Hz, 5H),2.29 (m, at 2.44 min, 1H), 1.26 (t, J = 7.6 Hz, 3H). 202 nm 17-14 1H NMR(400 MHz, Methanol-d4) δ 2.20-2.30 (s, 4H), 2.35- System 4 m/z 308 2.65(m, 2H), 2.81 (s, 3H), 3.76-4.15 (m, 4H), 6.36 (s, 1H) Method G (M + H)⁺(ES⁺), at 2.82 min, 254 nm 17-15 1H NMR (400 MHz, Methanol-d4) δ 1.89(brs, 1H), 2.21 (brs, System 2 m/z 328 1H), 2.40 (s, 3H,) 3.25-3.8(m,5H), 6.44 (s, 1H) Method E (M + H)⁺ (ES⁺), at 2.81 min, 245 nm 17-16 1HNMR (400 MHz, Methanol-d4) δ 2.78 (s, 3H), 4.18-4.20 (m, System 2 m/z314 3H), 4.47 (brs, 2H), 6.46 (s, 1H) Method E (M + H)⁺ (ES⁺), at 2.71min, 245 nm 17-17 1H NMR (400 MHz, Methanol-d4) δ 2.05-2.60 (m, 3H),2.69 (s, System 4 m/z 324 3H), 3.43-3.82 (m, 4H), 3.95 (s, 3H), 6.62 (s,1H) Method G (M + H)⁺ (ES⁺), at 2.71 min, 254 nm 18-1 1H NMR (400 MHz ,Methanol-d4) δ 2.37 (4H, s), 2.58-2.63 (1H, System 08 m/z 273 m), 2.85(3H, s), 3.75 (3H, s), 3.96 (1H, s), 4.05-4.07 (1H, m), 5.81 Method J(M + H)⁺ (ES⁺), (1H, s), 6.47 (1H, s), 7.67 (1H, s) at 1.91 min, 254 nm

BIOLOGICAL ACTIVITY Example A

H4 Antagonist Functional cAMP Gi Assay

HEKf cells were infected overnight using baculovirus expressing thehuman H4 receptor, then centrifuged at 1,200 rpm for 5 min, frozen incell freezing medium (Sigma) and stored at −150° C. On the day of assay,the cells were thawed and resuspended in HBSS with 500 nM IBMX toachieve a density of 1,500 cells/well. H4 ligands were prepared in DMSOand stamped by LabCyte ECHO acoustic dispensing at 25 nL in low volumeplates. 10 μL/well cells were plated in the presence of 1 μM forskolin,subjected to centrifugation at 1,200 rpm for 1 min and incubated for 30min prior to addition of Cisbio cAMP detection reagents to a totalvolume 20 μL/well. For the antagonist assay, cells were pre-incubatedwith H4 antagonist ligands for 30 min prior to addition of EC80concentration of histamine and a further 30 min incubation. Followingdetection reagent addition and shaking at room temperature for 60 min,cAMP accumulation was measured using HTRF on a PheraStar plate reader.EC50 values were generated using a 4-parameter logistical fit equationto quantify agonist potencies. Functional antagonist affinity valueswere generated using the Cheng-Prusoff equation to calculate a pKb valueusing the antagonist assay data.

H4 Antagonist Functional Dynamic Mass Redistribution Assay

HEKf cells were infected using baculovirus expressing the human H4receptor, plated into fibronectin-coated EPIC plates at a density of10,000 cells/well and incubated overnight at 37° C. The medium on cellswas changed to 30 μL HBSS with 20 mM HEPES per well and 30 nL DMSO wereadded per well by LabCyte ECHO acoustic dispensing. Following 2 hequilibration at room temperature, 30 nL of H4 ligands prepared in DMSOwere stamped by LabCyte ECHO acoustic dispensing into seeded EPIC platesand cellular dynamic mass redistribution was monitored using a CorningEPIC plate reader. Following 45 min measurement, 30 nL/well of histamineEC80 was added and monitored to obtain antagonist assay data. Maximumbaseline-corrected responses in μm were used to generate concentrationresponse curves. EC50 values were generated using a 4-parameterlogistical fit equation to quantify agonist potencies. Functionalantagonist affinity values were generated using the Cheng-Prusoffequation to calculate a pKb value using the antagonist assay data.

hERG Assay

hERG assay data was determined by Metrion Biosciences, Cambridge, UK,using the experimental protocols detailed below:

A Chinese Hamster Ovary (CHO) cell line stably expressing the humanether-á-go-go related gene was grown and passaged under standard cultureconditions. Cells were prepared for assays using dissociation protocolsdesigned to optimise cell health, yield, and seal and assay quality.Test samples were provided as 10 mM stock solutions in 100% DMSO. Allsample handling and serial dilutions were performed using glasscontainers and glass-lined plates. Atop working concentration of 30 μMwas prepared from the 10 mM sample stock solution using a 1:333-folddilution into external recording solution (0.3% DMSO v/v). In thesingle-concentration assay, test samples were screened at 30 μM againsta minimum of three separate cells. In the pIC₅₀ assay, test samples werescreened at 1, 3, 10 and 30 μM against a minimum of three separatecells. Each four-point concentration-response curve was constructedusing cumulative double sample additions of each concentration to thesame cell.

All experiments were performed on the QPatch gigaseal automated patchclamp platform. The composition of external and internal recordingsolutions for the QPatch experiments is shown in Table A below. Allsolutions were filtered (0.2 μm) prior to each experiment.

TABLE A The composition of external and internal solutions (in mM) usedin the hERG study Intracellular Extracellular Solution SolutionConstituent (mM) (mM) NaCl — 140  KCl 70 2 KF 60 — HEPES 10 10  MgCl₂ —1 CaCl₂ — 2 Glucose — 5 EGTA  5 — MgATP  5 — pH 7.2 (KOH) 7.4 (NaOH)

All recordings were made in the conventional whole-cell configurationand performed at room temperature (˜21° C.) using standard single holechips (Rchip 1.5-4 MΩ). Series resistance (4-15 MΩ) was compensatedby >80%. Currents were elicited from a holding potential of −90 mV usingthe industry standard “+40/−40” voltage protocol as shown in Figure Abelow; this was applied at a stimulus frequency of 0.1 Hz.

On achieving the whole-cell configuration, vehicle (0.3% DMSO v/v inexternal recording solution) was applied to each cell in two bolusadditions with a two-minute recording period between each addition toallow stable recordings to be achieved. Following the vehicle period,either:

-   -   i) For the single concentration assay—a single concentration of        test sample was applied at 30 μM as five bolus additions per        test concentration at two-minute intervals; or    -   ii) For the pIC₅₀ assay—four concentrations of test sample were        applied from 1 μM to 30 μM as two bolus additions per test        concentration at two-minute intervals;

and then the effects on hERG tail current amplitude were measured duringthe four-minute recording period. For each sweep of the voltageprotocol, membrane current and the passive properties of the individualcells were recorded by the QPatch assay software (version 5.0). Peakoutward tail current amplitude elicited during the test pulse to −40 mVwas measured relative to the instantaneous leak current measured duringthe initial pre-pulse step to −40 mV. For QC purposes, the minimumcurrent amplitude for the assay is >200 pA peak outward current,measured at the end of the vehicle period. The QPatch analysis softwarecalculates the mean peak current for the last three sweeps at the end ofeach concentration application period and the data is exported to Exceland interrogated using a bioinformatics suite developed running inPipeline Pilot (Biovia, USA). The template calculates percent inhibitionfor each test concentration application period as the reduction in meanpeak current or charge relative to the value measured at the end of thecontrol (i.e. vehicle) period. The percent inhibition values from eachcell are used to construct concentration-response curves employing afour-parameter logistic fit with 0 and 100% inhibition levels fixed atvery low and very high concentrations, respectively, and a free Hillslope factor. The IC₅₀ (50% inhibitory concentration) and Hillcoefficient are then determined, but only data from cells with Hillslopes within 0.5>nH<2.0 are included. The IC₅₀ data reported belowrepresents the mean of at least three separate cells (N≥3). Byconvention, a test sample that fails to achieve >40% block at the topconcentration will yield an ambiguous IC₅₀ value due to a poor orunconstrained fit. In this instance an arbitrary IC₅₀ value is returnedthat is 0.5 log unit above the highest concentration tested. Forexample, if a sample fails to demonstrate a mean inhibition of >40%block at a top concentration of 30 μM then an IC₅₀ value of 100 μM isreported, i.e. pIC₅₀≤4.0.

For compounds containing a pyrrolidine amine, the vast majority ofexamples have been prepared as single enantiomers with(R)-stereochemistry. Some compounds, however, have been prepared asracemates and then the enantiomers have been separated using thetechniques of chiral HPLC or chiral SFC. For these compounds, isomerassignment (Isomer 1, Isomer 2) is based on the retention time of thecompound using the separation technique that was performed in the finalchiral separation step. By implication, this could be chiral HPLC orchiral SFC retention time, and this will vary from compound to compound.

TABLE 4 H4 and hERG Activity Table 4 hERG Activity H4 AntagonistActivity hERG Human H4 Human H4 hERG % inhibition Ex. No. cAMP fpK_(b)DMR fpK_(b) pIC₅₀ at 30 μM Thioperamide ¹ 7.2 6.5 — — JNJ-7777120 ² 8.08.5 ≤4.0 — JNJ-39758979 ³ 8.1 8.5 ≤4.0 — Toreforant ⁴ 7.7 7.9   5.5 89PF-3893787 ⁵ 9.1 9.1   5.1 67 Compound 61 ⁶ 9.0 9.1   5.2 — Compound 48⁷ 8.1 9.0 — 55 1-1 7.3 — ≤4.0 — 1-2 6.1 — — — 2-1 7.4 — ≤4.0 — 2-2 7.3 —— 99 3-1 8.1 — — <1 3-2 7.0 — — 39 3-3 7.3 — — — 3-4 7.2 — — 45 3-5 7.0— — 19 4-1 8.9 9.3 ≤4.0 14 4-2 8.0 — — 25 4-3 8.9 8.9 — 34 4-4 7.1 — —14 4-5 8.0 8.6 — 18 5-1 6.4 — — — 5-2 6.4 — — 71 6-1 7.7 — — 12 6-2 7.4— — 94 7-1 8.2 7.7 — 14 7-2 9.6 — — 39 7-3 7.5 7.7 — — 7.4 8.2 — — 167-5 — — — — 7-6 6.4 — — — 7-7 8.7 — — 30 7-8 6.9 — — — 8-1 7.0 — ≤4.0 —8-2 7.5 8.9 — 13 8-3 7.4 — — 12 8-4 7.3 7.7 — 54 8-5 6.6 — — 77 8-6 7.7—   5.2 — 8-7 8.5 8.4   4.5 49 8-8 6.4 — — 44 8-9 6.2 — — — 8-10 6.9 6.9≤4.0 — 8-11 6.3 — — — 8-12 6.1 — — — 8-13 6.7 — — — 8-14 6.1 — — — 8-158.6 — ≤4.0 44 8-16 9.1 8.8 <4  33 8-17 7.3 — — 10 8-18 6.3 — — — 9-1 8.18.4 ≤4.0 — 9-2 7.9 — — 12 9-3 7.8 7.8 — 24 9-4 7.6 — — 17 9-5 7.4 — — —9-6 8.2 8.6 — 18 9-7 7.8 8.0 — 12 10-1 7.3 7.4 — 21 11-1 7.9 8.6 ≤4.0  211-2 7.1 7.1 — 20 11-3 6.3 — — 34 11-4 6.5 — — 46 11-5 6.1 — — — 11-68.2 8.4 — 90 11-7 Isomer 2 6.2 — — — 11-8 Isomer 1 6.6 — — 28 11-8Isomer 2 7.9 8.1 — 34 12-1 8.1 8.6 ≤4.0 — 12-2 6.6 — — 14 12-3 7.8 8.2 —47 12-4 6.8 — —  1 13-1 7.7 8.3 —  7 14-1 7.7 7.9 — — 15-1 8.5 — — 6815-2 — 8.0 — — 16-1 7.5 — — 32 16-2 7.3 — —  9 16-3 8.1 — — — 16-4 6.4 —— — 16-5 7.7 — — — 16-6 6.2 — — — 16-7 — 8.2 ≤4.0 — 16-8 — 7.6 — — 16-9— 7.7 — — 16-10 7.9 — — 21 16-11 8.1 — — 27 16-12 9.4 9.9 — 45 16-13 —8.3 — — 16-14 — 7.6 — — 17-1 — 8.8 ≤4.5 — 17-2 8.3 — — 39 17-3 — 8.4 — —17-4 — 8.3 — 39 17-5 — 9.1   4.6 — 17-6 — 7.9 — — 17-7 — 7.5 — 38 17-8 —7.4 — — 17-9 — 8.4 — — 17-10 9.6 — — 57 17-11 — 8.5 — — 17-12 8.8 — — 6017-13 — 7.3 — — 17-14 10.2  — — 44 17-15 10.3  — — 75 17-16 — 8.2 — —17-17 — 8.3 — 49 18-1 — 9.2 — — ¹ Changlu Liu et al, J Pharmacol ExpTher., 299, (2001), 121-130. ² Jennifer D. Venable et al, J. Med. Chem.,48, (2005), 8289-8298. ³ Brad M. Savall et al, J. Med. Chem., 57,(2014), 2429-2439. ⁴ Robin L Thurmond et al, Ann Pharmacol Pharm., 2,(2017), 1-11. ⁵ Charles E. Mowbray et al, Bioorg. Med. Chem. Lett., 21,(2011), 6596-6602. ⁶ Rogier A. Smits et al, Bioorg. Med. Chem. Lett.,23, (2013), 2663-2670. ⁷ Chan-Hee Park et al, J. Med. Chem., 61, (2018),2949-2961.

1. A compound of the formula (1):

or a salt thereof, wherein; X is CH or N; n is 1 or 2; R¹ is selectedfrom H or C₁₋₃ alkyl, wherein the C₁₋₃ alkyl group may be cyclised backonto the ring to which NHR¹ is attached to form a second ring; R² is Hor methyl; and A represents an optionally substituted pyrazole ringwhich is linked to the ring containing X by a carbon-carbon bond.
 2. Thecompound according to claim 1, wherein X is N.
 3. The compound accordingto claim 1 or claim 2, wherein R¹ is H or methyl.
 4. The compoundaccording to any one of claims 1 to 3, wherein R² is H.
 5. The compoundaccording to claim 1 which is a compound of formula (2a), (2b) or (2c):

or a salt thereof.
 6. The compound according to claim 5 which is acompound of formula (3a), (3b) or (3c):

or a salt thereof.
 7. The compound according to claim 1 which is acompound of formula (2d) or (2e):

or a salt thereof.
 8. The compound according to any one of claims 1 to 7wherein A is an optionally substituted pyrazole ring selected from

wherein R³ is selected from H; a C₁₋₆ non-aromatic hydrocarbon groupoptionally substituted with 1 to 6 fluorine atoms; (CH₂)_(m)R⁶, whereinm is 1 to 3 and R⁶ is selected from CN, OH, C₁-C₃ alkoxy and a group SR⁸or oxidized forms thereof, wherein R⁸ is C₁-C₃ alkyl; an optionallysubstituted 4 to 6 membered saturated heterocyclic ring containing 1heteroatom selected from O and N, wherein the optional substituent isCO₂R⁷, wherein R⁷ is C₁₋₃ alkyl; wherein R⁴ and R⁵ are independentlyselected from: a C₁₋₆ non-aromatic hydrocarbon group optionallysubstituted with 1 to 6 fluorine atoms; (CH₂)_(p)R⁹, wherein p is 0 to 3and R⁹ is selected from CN, halo, OH, C₁-C₃ alkoxy and a group SR⁸ oroxidized forms thereof, wherein R⁸ is C₁-C₃ alkyl; or R⁴ and R⁵ may beoptionally joined to form a fused 5 or 6 membered ring; or R⁴ and R³ maybe optionally joined to form a fused 5 or 6 membered ring.
 9. Thecompound according to claim 8 wherein R³ is selected from H, methyl,CF₃, CF₂H, ethyl, cyclopropyl, cyclobutyl, CH₂CF₃, CH₂CH₂OH, CH₂CH₂OCH₃,CH₂CH₂CN, CH₂CN, oxetane, ethyl-piperidine-carboxylate or R⁴ and R³ arejoined to form a fused 5 membered aliphatic ring.
 10. The compoundaccording to claim 8 or claim 9 wherein R⁴ or R⁵ is selected frommethyl, ethyl, cyclopropyl, cyclobutyl, propyl, isopropyl, CF₃, CF₂H,fluoro, chloro, bromo, cyano, methoxy, or R⁴ and R⁵ are joined to form afused 5 or 6 membered ring or R⁴ and R³ are joined to form a fused 5membered aliphatic ring.
 11. The compound according to any one of claims1 to 10 wherein A is selected from the group consisting of:


12. The compound according to claim 11 wherein A is:


13. The compound according to claim 1 which is selected from the groupconsisting of:

or a salt thereof.
 14. The compound according to claim 1 which is:


15. The compound according to claim 1 which is:


16. The compound according to claim 1 which is:


17. The compound according to claim 1 which is:


18. The compound according to claim 1 which is:


19. The compound according to any one of claims 1 to 18 having H4receptor activity.
 20. The compound according to claim 19 which exhibitslow hERG activity.
 21. A pharmaceutical composition comprising acompound as defined in any one of claims 1 to 20 and a pharmaceuticallyacceptable excipient.
 22. The compound or composition according to anyone of claims 1 to 21 for use in medicine.
 23. The compound orcomposition according to any one of claims 1 to 21 for use in thetreatment of inflammatory disorders including asthma, chronic pruritus,dermatitis, rheumatoid arthritis, gastric ulcerogenesis and colitis.